Relationship between β-amyloid and structural network topology in decedents without dementia

Researchers from Amsterdam UMC – location VUmc published a post-mortem MRI and histology study in non-neurological controls from the Normal Aging Brain Collection (NABCA). The researchers aimed to elucidate the relationship between amyloid-β protein aggregations and network topology in decendents not meeting the pathological criteria for neurodegenerative disease (e.g. Alzheimer’s disease). The study highlights the potential importance of posterior cingulate cortex and precuneus network topology as an early marker of Aβ pathologic change. The manuscript is published in Neurology.

 

Relationship between β-amyloid and structural network topology in decedents without dementia

 

Abstract

Objective: To investigate the association between β-amyloid (Aβ) load and postmortem structural network topology in decedents without dementia.

Methods: Fourteen decedents (mean age at death 72.6 ± 7.2 years) without known clinical diagnosis of neurodegenerative disease and meeting pathology criteria only for no or low Alzheimer disease (AD) pathologic change were selected from the Normal Aging Brain Collection Amsterdam database. In situ brain MRI included 3D T1-weighted images for anatomical registration and diffusion tensor imaging for probabilistic tractography with subsequent structural network construction. Network topologic measures of centrality (degree), integration (global efficiency), and segregation (clustering and local efficiency) were calculated. Tissue sections from 12 cortical regions were sampled and immunostained for Aβ and hyperphosphorylated tau (p-tau), and histopathologic burden was determined. Linear mixed effect models were used to assess the relationship between Aβ and p-tau load and network topologic measures.

Results: Aβ was present in 79% of cases and predominantly consisted of diffuse plaques; p-tau was sparsely present. Linear mixed effect models showed independent negative associations between Aβ load and global efficiency (β = -0.83 × 10-3p = 0.014), degree (β = -0.47, p = 0.034), and clustering (β = -0.55 × 10-2p = 0.043). A positive association was present between Aβ load and local efficiency (β = 3.16 × 10-3p = 0.035). Regionally, these results were significant in the posterior cingulate cortex (PCC) for degree (β = -2.22, p < 0.001) and local efficiency (β = 1.01 × 10-2p = 0.014) and precuneus for clustering (β = -0.91 × 10-2p = 0.017). There was no relationship between p-tau and network topology.

Conclusion: This study in deceased adults with AD-related pathologic change provides evidence for a relationship among early Aβ accumulation, predominantly of the diffuse type, and structural network topology, specifically of the PCC and precuneus.

Axonal degeneration as substrate of fractional anisotropy abnormalities in multiple sclerosis cortex

Researchers from Amsterdam UMC – location VUmc and Vita-Salute San Raffaele University in Milan have collaborated on a post-mortem MRI and histology study in multiple sclerosis (MS) and Normal Aging Brain Collection (NABCA) donors. The researchers aimed to define the histopathological substrates of diffusivity abnormalities in the cortex of MS patients and non-neurological donors. The manuscript is published in Brain. 

 

Axonal degeneration as substrate of fractional anisotropy abnormalities in multiple sclerosis cortex

Abstract

Cortical microstructural abnormalities are associated with clinical and cognitive deterioration in multiple sclerosis. Using diffusion tensor MRI, a higher fractional anisotropy has been found in cortical lesions versus normal-appearing cortex in multiple sclerosis. The pathological substrates of this finding have yet to be definitively elucidated. By performing a combined post-mortem diffusion tensor MRI and histopathology study, we aimed to define the histopathological substrates of diffusivity abnormalities in multiple sclerosis cortex. Sixteen subjects with multiple sclerosis and 10 age- and sex-matched non-neurological control donors underwent post-mortem in situ at 3 T MRI, followed by brain dissection. One hundred and ten paraffin-embedded tissue blocks (54 from multiple sclerosis patients, 56 from non-neurological controls) were matched to the diffusion tensor sequence to obtain regional diffusivity measures. Using immunohistochemistry and silver staining, cortical density of myelin, microglia, astrocytes and axons, and density and volume of neurons and glial cells were evaluated. Correlates of diffusivity abnormalities with histological markers were assessed through linear mixed-effects models. Cortical lesions (77% subpial) were found in 27/54 (50%) multiple sclerosis cortical regions. Multiple sclerosis normal-appearing cortex had a significantly lower fractional anisotropy compared to cortex from non-neurological controls (P = 0.047), whereas fractional anisotropy in demyelinated cortex was significantly higher than in multiple sclerosis normal-appearing cortex (P = 0.012) but not different from non-neurological control cortex (P = 0.420). Compared to non-neurological control cortex, both multiple sclerosis normal-appearing and demyelinated cortices showed a lower density of axons perpendicular to the cortical surface (P = 0.012 for both) and of total axons (parallel and perpendicular to cortical surface) (P = 0.028 and 0.012). In multiple sclerosis, demyelinated cortex had a lower density of myelin (P = 0.004), parallel (P = 0.018) and total axons (P = 0.029) versus normal-appearing cortex. Regarding the pathological substrate, in non-neurological controls, cortical fractional anisotropy was positively associated with density of perpendicular, parallel, and total axons (P = 0.031 for all). In multiple sclerosis, normal-appearing cortex fractional anisotropy was positively associated with perpendicular and total axon density (P = 0.031 for both), while associations with myelin, glial and total cells and parallel axons did not survive multiple comparison correction. Demyelinated cortex fractional anisotropy was positively associated with density of neurons, and total cells and negatively with microglia density, without surviving multiple comparison correction. Our results suggest that a reduction of perpendicular axons in normal-appearing cortex and of both perpendicular and parallel axons in demyelinated cortex may underlie the substrate influencing cortical microstructural coherence and being responsible for the different patterns of fractional anisotropy changes occurring in multiple sclerosis cortex.

 

Review on post-mortem MRI and histology studies in neurologic disease

Researchers from Amsterdam UMC – location VUmc and Leiden University, have recently written an invited review on post-mortem MRI and histology studies in multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD) and traumatic brain injury (TBI), and their relevance as radiological (bio)markers for the clinical (research) setting. The manuscript is published in Neuroscience Bulletin.

Post-mortem MRI and histology studies in neurologic disease: a translational approach

Abstract

In this review, combined post-mortem brain magnetic resonance imaging (MRI) and histology studies are highlighted, illustrating the relevance of translational approaches to define novel MRI signatures of neuropathological lesions in neuroinflammatory and neurodegenerative disorders. Initial studies combining post-mortem MRI and histology have validated various MRI sequences, assessing their sensitivity and specificity as diagnostic biomarkers in neurologic disease. More recent studies have focused on defining new radiological (bio)markers and implementing them in the clinical (research) setting. By combining neurological and neuroanatomical expertise with radiological development and pathological validation, a cycle emerges that allows for the discovery of novel MRI biomarkers to be implemented in vivo. Examples of this cycle are presented for multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury. Some applications have been shown to be successful, while others require further validation. In conclusion, there is much to explore with post-mortem MRI and histology studies, which can eventually be of high relevance for clinical practice.

Normal Aging Brain Collection (NABCA) pipeline publication

We are proud to present the publication of our manuscript “Normal Aging Brain Collection Amsterdam (NABCA): A comprehensive collection of postmortem high-field imaging, neuropathological and morphometric datasets of non-neurological controls.” In open access journal Neuroimage: Clinical. We would like to thank everyone who has contributed to this publication.

Click on this link to go to the manuscript.

Abstract

Well-characterized, high-quality brain tissue of non-neurological control subjects is a prerequisite to study the healthy aging brain, and can serve as a control for the study of neurological disorders. The Normal Aging Brain Collection Amsterdam (NABCA) provides a comprehensive collection of post-mortem (ultra-)high-field MRI (3Tesla and 7 Tesla) and neuropathological datasets of non-neurological controls. By providing MRI within the pipeline, NABCA uniquely stimulates translational neurosciences; from molecular and morphometric tissue studies to the clinical setting. We describe our pipeline, including a description of our on-call autopsy team, donor selection, in situ and ex vivo post-mortem MRI protocols, brain dissection and neuropathological diagnosis. A demographic, radiological and pathological overview of five selected cases on all these aspects is provided. Additionally, information is given on data management, data and tissue application procedures, including review by a scientific advisory board, and setting up a material transfer agreement before distribution of tissue. Finally, we focus on future prospects, which includes laying the foundation for a unique platform for neuroanatomical, histopathological and neuro-radiological education, of professionals, students and the general (lay) audience.

7T MRI allows detection of disturbed cortical lamination of the medial temporal lobe in patients with Alzheimer’s disease.

A collaborative effort from researchers at Leiden University and Amsterdam UMC, have led to the publication of a post-mortem MRI and histology manuscript, published in Neuroimage: Clinical. 

“7T MRI allows detection of disturbed cortical lamination of the medial temporal lobe in patients with Alzheimer’s disease” (open access)

Abstract

Using 7T T2*-weighted imaging, we scanned post-mortem hemispheres of Alzheimer patients and age-matched controls to describe the patterns of appearance of cortical lamination on T2*-weighted MRI in the medial temporal lobe and to assess the changes in Alzheimer patients versus controls. While controls showed a hypointense line of Baillarger in the majority of the cases, appearance of cortical lamination varied to a greater extent in the Alzheimer patients. Severely distorted cortical lamination was also observed in advanced stage Alzheimer patients and presented itself as a broad hypointense inhomogeneous band, covering a large part of the cortical width. Histology indicated that the changes in the appearance of visible cortical lamination were not only associated with myelin changes, but also with diffuse cortical iron alterations and depositions. Therefore, imaging cortical lamination alterations in Alzheimer patients using T2*-weighted MRI might provide new information on involved neuroanatomical structures in an advanced neurodegenerative stage.

Structural network topology relates to tissue properties in multiple sclerosis

Researchers from the department of Anatomy and Neurosciences, Amsterdam UMC – location VUmc have combined MRI and histology to determine the the micro-scale correlates of macro-scale network measures of segregation and integration in multiple sclerosis.

 

https://www.ncbi.nlm.nih.gov/pubmed/30467603

OBJECTIVE:

Abnormalities in segregative and integrative properties of brain networks have been observed in multiple sclerosis (MS) and are related to clinical functioning. This study aims to investigate the micro-scale correlates of macro-scale network measures of segregation and integration in MS.

METHODS:

Eight MS patients underwent post-mortem in situ whole-brain diffusion tensor (DT) imaging and subsequent brain dissection. Macro-scale structural network topology was derived from DT data using graph theory. Clustering coefficient and mean white matter (WM) fiber length were measures of nodal segregation and integration. Thirty-three tissue blocks were collected from five cortical brain regions. Using immunohistochemistry micro-scale tissue properties were evaluated, including, neuronal size, neuronal density, axonal density and total cell density. Nodal network properties and tissue properties were correlated.

RESULTS:

A negative correlation between clustering coefficient and WM fiber length was found. Higher clustering coefficient was associated with smaller neuronal size and lower axonal density, and vice versa for fiber length. Higher whole-brain WM lesion load was associated with higher whole-brain clustering, shorter whole-brain fiber length, lower neuronal size and axonal density.

CONCLUSION:

Structural network properties on MRI associate with neuronal size and axonal density, suggesting that macro-scale network measures may grasp cortical neuroaxonal degeneration in MS.

Detailed structural orchestration of Lewy pathology in Parkinson’s disease as revealed by 3D multicolor STED microscopy

Colleagues from the department of Anatomy and Neurosciences, Amsterdam UMC – location VUmc, have recently published on post-translational modifications of alpha-synuclein (aSyn), in particular phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT) in Parkinson’s disease (PD). Read the manuscript, with exceptional pictures, here: https://www.biorxiv.org/content/early/2018/11/14/470476

Erasmus MC – VUmc collaboration discover new gene involved in the development of Parkinson’s disease and dementia with Lewy bodies

An international team led by Prof. Vincenzo Bonifati from the Erasmus MC Rotterdam, Department of Clinical Genetics, has discovered for the first time variants in a gene (termed LRP10) in patients with familial forms of Parkinson’s disease, Parkinson’s disease and dementia, and Dementia with Lewy bodies. The paper reporting this discovery will be published in The Lancet Neurology this week. ‘This discovery opens a novel window on the molecular mechanisms of these common neurodegenerative diseases, and might pave the way to the identification of novel biomarkers and novel disease-modifying therapies’, says Prof. Bonifati.

 

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