Helmut Heinsen

University of Würzburg

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Lea T. Grinberg

University of California, San Francisco

Stefan Teipel

University of Rostock

Udo Rüb

Goethe University Frankfurt

Michel J. Grothe

Fundacion Centro De Investigacion De Enfermedades Neurologicas

Christoph Schmitz

LMU Klinikum

H. Beckmann

Central Institute of Mental Health

Horst‐Werner Korf

Heinrich Heine University Düsseldorf

Peter Riederer

University of Würzburg

William W. Seeley

University of California, San Francisco

Eduardo Joaquim Lopes Alho

Universidade de São Paulo

Cooperative Institutions

University of Würzburg

159

University of California, San Francisco

114

Universidade de São Paulo

Ludwig-Maximilians-Universität München

University Memory and Aging Center

Digital Proteomics (United States)

Harvard University

Goethe University Frankfurt

Charité - Universitätsmedizin Berlin

University College London

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Validation of locus coeruleus histological reconstructions to MRI

Alzheimer s & Dementia (2021)

Tia LaMore Yuheng Chen Song Li Duygu Tonsun Maria Concepción García Otaduy

Abstract Background The Locus coeruleus(LC) is one of the first sites of tau aggregation and suffers from dramatic volume loss early on. Due to the shrinking of the LC preceding the onset of clinical symptoms of AD by decades, a precise understanding of the neurobiological correlates of MRI signal may turn LC neuroimaging into an early non‐invasive staging biomarker for AD. Though there are many efforts to image the LC in‐vivo, first, it is vital to confirm postmortem validation of the MRI signal. In this study, we are attempting to validate postmortem histological reconstructions of the LC to its corresponding postmortem MRI reconstructions, voxel‐to‐voxel. Method We used a pipeline developed in‐house employing brainstem processing, staining, and computer‐based algorithms for 2D and 3D registration to reconstruct the histological volume of the brainstem with structural detail. This pipeline allows for precise alignment of histology‐based cytoarchitectural 3Dreconstructions (Fig. 1A) of the brainstem to its 7T‐MRI counterpart (Fig. 1B). Photoshop and Freeview were used to manually segment the LC in digital images of cross sections of the brainstem labeled with Nissl staining (Fig. 2), to generate 2D LC masks in all 4 cases. We then registered the stained cross sections and their corresponding LC masks to the cross sections’ blockface to correct for any deformation of tissue during the staining process. We applied Freeview commands to reconstruct the 3D brainstems and their 3D LC masks. We registered the resulting 3D reconstruction and LC mask to matching MRI coordinates, enabling voxel‐to‐voxel comparisons. We will continue to demonstrate the value of our pipeline in regards to validating neuroimaging methods in AD with these structural masks of the postmortem LC registered to the MRI counterpart in 3 more cases. Result The histological 3D LC masks were registered onto the parallel 3D MRIs. In Freeview, we plan to run correlation analysis with an output of dice coefficient ranging from 0‐1, with a coefficient of 1 translating to the voxels of the LC masks and the MRI signal overlapping exactly. Conclusion Our pipeline enables voxel‐to‐voxel correlation analysis between histology and MRI scans for validation of LC neuroimaging. Current finalization of 3 other cases is ongoing.

Locus coeruleus

Nissl body

Voxel-based morphometry

10.1002/alz.055774

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Teaching NeuroImages: In vivo visualization of Edinger comb and Wilson pencils

Neurology (2019)

Andreas Horn Siobhán Ewert Eduardo Joaquim Lopes Alho Markus Axer Helmut Heinsen

The "direct" and "indirect" pathways play crucial roles in movement disorder pathophysiology. Both traverse from the striatum to the internal pallidum and substantia nigra, the latter detouring to external pallidum and subthalamic nucleus. Anatomically, the pathways manifest within the striatofugal bundle that passes radially through the pallidum in the form of pencil-like tracts (first described by Wilson1; figure 1) before leaving the pallidum toward the substantia nigra in the form of a comb described by Edinger in 18962 (figure 2). A century later, these structures can be visualized in the living human brain (figures 1D and 2A).

Subthalamic Nucleus

Ventral pallidum

10.1212/wnl.0000000000007252

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Citations (17)

Serial Thick, Frozen, Gallocyanin Stained Sections of Human Centrl Nervous System

Journal of Histotechnology (1991)

Helmut Heinsen

AbstractA rapid method for macroscopic and microscopic investigation of human CNS is proposed. After formalin fixation, gelatin or agarose embedding, and cryoprotective treatment, frozen human spinal cords, brainstems, or hemispheres can be serially cut into 0.7 mm thick slices. Stained with gallocyanin- chromalum, these slices facilitate cytoarchitectonic, neuropathologic, and quantitative examination. Regions of interest from parallel formalin-stored unstained slices can be embedded into paraffin and stained by any immunocytologic and histologic stain compatible with formalin fixation and paraffin embedding. (The J Histotechnol 14:167, 1991)Keywords: CNScomparative anatomycytoarchitectonicsneuroimagingneuropathologyNissl stainquantitative

10.1179/014788891794667005

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Citations (3)

Degeneration of the Cerebellum in Huntington's Disease (HD): Possible Relevance for the Clinical Picture and Potential Gateway to Pathological Mechanisms of the Disease Process

Brain Pathology (2012)

Udo Rüb Franziska Hoche E. R. Brunt Helmut Heinsen Kay Seidel

Abstract H untington's disease ( HD ) is a polyglutamine disease and characterized neuropathologically by degeneration of the striatum and select layers of the neo‐ and allocortex. In the present study, we performed a systematic investigation of the cerebellum in eight clinically diagnosed and genetically confirmed HD patients. The cerebellum of all HD patients showed a considerable atrophy, as well as a consistent loss of P urkinje cells and nerve cells of the fastigial, globose, emboliform and dentate nuclei. This pathology was obvious already in HD brains assigned V onsattel grade 2 striatal atrophy and did not correlate with the extent and distribution of striatal atrophy. Therefore, our findings suggest (i) that the cerebellum degenerates early during HD and independently from the striatal atrophy and (ii) that the onset of the pathological process of HD is multifocal. Degeneration of the cerebellum might contribute significantly to poorly understood symptoms occurring in HD such as impaired rapid alternating movements and fine motor skills, dysarthria, ataxia and postural instability, gait and stance imbalance, broad‐based gait and stance, while the morphological alterations (ie ballooned neurons, torpedo‐like axonal inclusions) observed in the majority of surviving nerve cells may represent a gateway to the unknown mechanisms of the pathological process of HD .

Cerebellar ataxia

10.1111/j.1750-3639.2012.00629.x

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Citations (133)

Stereological assessment of the dorsal anterior cingulate cortex in schizophrenia: absence of changes in neuronal and glial densities

Neuropathology and Applied Neurobiology (2012)

Malin Höistad Helmut Heinsen Bridget Wicinski Christoph Schmitz P. R. Hof

M. Höistad, H. Heinsen, B. Wicinski, C. Schmitz and P. R. Hof (2013) Neuropathology and Applied Neurobiology 39, 348–361 Stereological assessment of the dorsal anterior cingulate cortex in schizophrenia: absence of changes in neuronal and glial densities Aims: The prefrontal and anterior cingulate cortices are implicated in schizophrenia, and many studies have assessed volume, cortical thickness, and neuronal densities or numbers in these regions. Available data, however, are rather conflicting and no clear cortical alteration pattern has been established. Changes in oligodendrocytes and white matter have been observed in schizophrenia, introducing a hypothesis about a myelin deficit as a key event in disease development. Methods: We investigated the dorsal anterior cingulate cortex (dACC) in 13 men with schizophrenia and 13 age‐ and gender‐matched controls. We assessed stereologically the dACC volume, neuronal and glial densities, total neurone and glial numbers, and glia/neurone index (GNI) in both layers II–III and V–VI. Results: We observed no differences in neuronal or glial densities. No changes were observed in dACC cortical volume, total neurone numbers, and total glial numbers in schizophrenia. This contrasts with previous findings and suggests that the dACC may not undergo as severe changes in schizophrenia as is generally believed. However, we observed higher glial densities in layers V–VI than in layers II–III in both controls and patients with schizophrenia, pointing to possible layer‐specific effects on oligodendrocyte distribution during development. Conclusions: Using rigorous stereological methods, we demonstrate a seemingly normal cortical organization in an important neocortical area for schizophrenia, emphasizing the importance of such morphometric approaches in quantitative neuropathology. We discuss the significance of subregion‐ and layer‐specific alterations in the development of schizophrenia, and the discrepancies between post mortem histopathological studies and in vivo brain imaging findings in patients.

Cingulate cortex

Stereology

10.1111/j.1365-2990.2012.01296.x

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Citations (29)

Degeneration of Select Motor and Limbic Nuclei of the Thalamus in Huntington’s Disease (HD)

Advances in anatomy, embryology and cell biology (2015)

Udo Rüb Jean Paul Vonsattel Helmut Heinsen Horst‐Werner Korf

Subthalamic Nucleus

10.1007/978-3-319-19285-7_4

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Citations (1)

Changes in the expression of genes related to neuroinflammation over the course of sporadic Alzheimer’s disease progression: CX3CL1, TREM2, and PPARγ

Journal of Neural Transmission (2015)

Sabrina Strobel Edna Grünblatt P. Riederer Helmut Heinsen Thomas Arzberger

TREM2

Pathogenesis

CX3CL1

10.1007/s00702-015-1369-5

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Citations (47)

Distribution pattern of monoamine oxidase a and monoamine oxidase b in human substantia nigra shown by immunofluorescence cytochemistry on thin frozen sections

Pharmacological Research Communications (1988)

G. Moll R. Moll Peter Riederer Helmut Heinsen R. M. Denney

Cytochemistry

Immunofluorescence

10.1016/s0031-6989(88)80556-3

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Citations (5)

Validation of high resolution subcortical MRI signal using voxel to voxel histology to neuroimaging correlation in AD continuum: advancing neuroimaging biomarker tools for early AD staging

Alzheimer s & Dementia (2023)

Tia LaMore Shuo Huang Yuheng Chen Song Hua Li Wing Hung Lee

Abstract Background Studies suggest a decrease in LC volume by 8% each Braak stage, starting at Braak 0‐1, while in normal aging the LC volume remains intact. Thus, LC volumetry is an attractive potential biomarker to monitor AD progression from precognitive stages. However, precise LC volumetry neuroimaging is challenging due to the LC’s small size and location in the brainstem that’s prone to artifacts. To validate the precision/utility of neuroimaging sequences designed for LC volumetry, we developed a pipeline allowing voxel‐to‐voxel histology to neuroimaging comparisons. We tested this pipeline to analyze the neuro‐histological counterpart of an LC volume obtained from manual segmentation from a MRI neuromelanin(NM)sensitive GRE image. Method Whole brain high resolution(0.7mm)3D‐T1 images and 2D‐2mm thick NM‐sensitive axial GRE images of the brainstem were obtained postmortem in situ before brain removal from a single subject using a 7T MRI(Siemens Magnetom). We combined celloidin‐based histological processing and 3D reconstructions of the histology volume at microscopic resolution which was then aligned to T1. We used structures visible in structural MRI(T1)(brainstem surface, red nucleus, and 4th ventricle) to calculate Dice coefficient to measure registration accuracy. Next, we performed an overlap percentage analysis to investigate how well GRE sequence detected LC borders compared to histology. Result We ran Dice coefficient analysis for brainstem structures to measure histology to MRI registration accuracy(Table1). The LC GRE to histology masks overlap percentage was 35.29% and 10.77% compared to the MRI and histology mask total voxels(voxel size = 0.34mm3). The overlap percentage obtained for the rostral and middle LC thirds ranged from 9.43% to 75%when compared to total voxels in MRI/histology masks, while the caudal third had zero overlap(Table2,Fig.1). Conclusion Our pipeline enables voxel‐to‐voxel correlation analysis between histology and high resolution LC MRIs for neuroimaging validation. The caudal third of the LC in our case has shown a clear lack of overlap potentially due to lack of signal specificity in MRI when compared to the gold standard that is histology. Current analysis of another five other cases is ongoing. Validation of LC MRI signal will inform interpretations of signal results in living patients with the potential to act as a diagnostic tool for ADRD.

Histology

10.1002/alz.080106

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Mean cell spacing abnormalities in the neocortex of patients with schizophrenia

Psychiatry Research (2005)

Manuel F. Casanova Leonie de Zeeuw Andrew E. Switala Paweł Kreczmański Hubert Korr

Neocortex

Neuropil

10.1016/j.psychres.2004.11.004

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Citations (30)