Helmut Heinsen

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, San Paulo, São Paulo, Brazil

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Publications (170)916.54 Total impact


  • No preview · Article · Jan 2016 · Parkinsonism & Related Disorders

  • No preview · Article · Jan 2016 · Parkinsonism & Related Disorders
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    ABSTRACT: In spite of considerable progress in neuropathological research on Alzheimer's disease (AD), knowledge regarding the exact pathoanatomical distribution of the tau cytoskeletal pathology in the thalamus of AD patients in the advanced Braak and Braak AD stages V or VI of the cortical cytoskeletal pathology is still fragmentary. Investigation of serial 100 μm-thick brain tissue sections through the thalamus of clinically diagnosed AD patients with Braak and Braak AD stage V or VI cytoskeletal pathologies immunostained with the anti-tau AT8 antibody, along with the affection of the extraterritorial reticular nucleus of the thalamus, reveals a consistent and severe tau immunoreactive cytoskeletal pathology in the limbic nuclei of the thalamus (e.g., paraventricular, anterodorsal and laterodorsal nuclei, limitans-suprageniculate complex). The thalamic nuclei integrated into the associative networks of the human brain (e.g., ventral anterior and mediodorsal nuclei) are only mildly affected, while its motor precerebellar (ventral lateral nucleus) and sensory nuclei (e.g., lateral and medial geniculate bodies, ventral posterior medial and lateral nuclei, parvocellular part of the ventral posterior medial nucleus) are more or less spared. The highly stereotypical and characteristic thalamic distribution pattern of the AD-related tau cytoskeletal pathology represents an anatomical mirror of the hierarchical topographic distribution of the cytoskeletal pathology in the interconnected regions of the cerebral cortex of AD patients. These pathoanatomical parallels support the pathophysiological concept of a transneuronal spread of the disease process of AD along anatomical pathways. The AD-related tau cytoskeletal pathology in the thalamus most likely contributes substantially to the neuropsychiatric disease symptoms (e.g., dementia), attention deficits, oculomotor dysfunctions, altered non-discriminative aspects of pain experience of AD patients, and the disruption of their waking and sleeping patterns.
    No preview · Article · Oct 2015 · Journal of Alzheimer's disease: JAD
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    ABSTRACT: The human brain undergoes non-uniform changes during aging. The substantia nigra (SN), the source of major dopaminergic pathways in the brain, is particularly vulnerable to changes in the progression of several age-related neurodegenerative diseases. To establish normative data for high-resolution imaging, and to further clinical and anatomical studies we analyzed SNs from 15 subjects aged 50-91 cognitively normal human subjects without signs of parkinsonism. Complete brains or brainstems with substantia nigra were formalin-fixed, celloidin-mounted, serially cut and Nissl-stained. The shapes of all SNs investigated were reconstructed using fast, high-resolution computer-assisted 3D reconstruction software. We found a negative correlation between age and SN volume (p = 0.04, rho = -0.53), with great variability in neuronal numbers and density across participants. The 3D reconstructions revealed SN inter- and intra-individual variability. Furthermore, we observed that human SN is a neuronal reticulum, rather than a group of isolated neuronal islands. Caution is required when using SN volume as a surrogate for SN status in individual subjects. The use of multimodal sequences including those for fiber tracts may enhance the value of imaging as a diagnostic tool to assess SN in vivo. Further studies with a larger sample size are needed for understanding the structure-function interaction of human SN.
    No preview · Article · Sep 2015 · Brain Structure and Function
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    ABSTRACT: The HUPO Brain Proteome Project (HUPO BPP) held its 23rd workshop in São Paulo, Brazil, April 16-17, 2015. The focus of the spring workshop was on strategies and predictive therapies concerning neurodegenerative diseases. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    No preview · Article · Sep 2015 · Proteomics
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    ABSTRACT: Alzheimer's disease (AD) represents the most frequent progressive neuropsychiatric disorder worldwide leading to dementia. We systematically investigated the presence and extent of the AD-related cytoskeletal pathology in serial thick tissue sections through all subcortical brain nuclei that send efferent projections to the transentorhinal and entorhinal regions in three individuals with Braak and Braak AD stage 0 cortical cytoskeletal pathology and fourteen individuals with Braak and Braak AD stage I cortical cytoskeletal pathology by means of immunostainings with the anti-tau antibody AT8. These investigations revealed consistent AT8 immunoreactive tau cytoskeletal pathology in a subset of these subcortical nuclei in the Braak and Braak AD stage 0 individuals and in all of these subcortical nuclei in the Braak and Braak AD stage I individuals. The widespread affection of the subcortical nuclei in Braak and Braak AD stage I shows that the extent of the early subcortical tau cytoskeletal pathology has been considerably underestimated previously. In addition, our novel findings support the concept that subcortical nuclei become already affected during an early 'pre-cortical' evolutional phase before the first AD-related cytoskeletal changes occur in the mediobasal temporal lobe (i.e. allocortical transentorhinal and entorhinal regions). The very early involved subcortical brain regions may represent the origin of the AD-related tau cytoskeletal pathology, from where the neuronal cytoskeletal pathology takes an ascending course toward the secondarily affected allocortex and spreads transneuronally along anatomical pathways in predictable sequences.
    No preview · Article · Jul 2015 · Brain Pathology

  • No preview · Article · Jul 2015

  • No preview · Article · Jul 2015

  • No preview · Article · Jul 2015
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    ABSTRACT: Brain function in normal aging and neurological diseases has long been a subject of interest. With current technology, it is possible to go beyond descriptive analyses to characterize brain cell populations at the molecular level. However, the brain comprises over 100 billion highly specialized cells, and it is a challenge to discriminate different cell groups for analyses. Isolating intact neurons is not feasible with traditional methods, such as tissue homogenization techniques. The advent of laser microdissection techniques promises to overcome previous limitations in the isolation of specific cells. Here, we provide a detailed protocol for isolating and analyzing neurons from postmortem human brain tissue samples. We describe a workflow for successfully freezing, sectioning and staining tissue for laser microdissection. This protocol was validated by mass spectrometric analysis. Isolated neurons can also be employed for western blotting or PCR. This protocol will enable further examinations of brain cell-specific molecular pathways and aid in elucidating distinct brain functions.
    No preview · Article · Jun 2015 · Journal of Neural Transmission
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    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia; however, mechanisms and biomarkers remain unclear. Here, we examined hippocampal CA4 and dentate gyrus subfields, which are less studied in the context of AD pathology, in post-mortem AD and control tissue to identify possible biomarkers. We performed mass spectrometry-based proteomic analysis combined with label-free quantification for identification of differentially expressed proteins. We identified 4,328 proteins, of which 113 showed more than 2-fold higher or lower expression in AD hippocampi than in control tissues. Five proteins were identified as putative AD biomarkers (MDH2, PCLO, TRRAP, YWHAZ, and MUC19 isoform 5) and were cross-validated by immunoblotting, selected reaction monitoring, and MALDI imaging. We also used a bioinformatics approach to examine upstream signalling interactions of the 113 regulated proteins. Five upstream signalling (IGF1, BDNF, ZAP70, MYC, and cyclosporin A) factors showed novel interactions in AD hippocampi. Taken together, these results demonstrate a novel platform that may provide new strategies for the early detection of AD and thus its diagnosis. Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, and its prevalence is estimated to increase twofold in industrialized countries and by four-fold in developing countries over the next 20 years 1. AD is characterized by a loss in connectivity in several brain fields in particular including the hippocampus. For instance, the density of synapses was significantly decreased in the outer molecular layer of the hippocampal dentate gyrus in AD 2. Notably, the hippocampus plays a key role in the neurodegenerative events occurring in AD, since changes in this field are closely associated with memory loss and cognitive impairment 3. Despite recent progress in understanding the mechanism of AD, our knowledge of the molecular details regarding this disease is still incomplete.
    Full-text · Article · Jun 2015 · Scientific Reports

  • No preview · Conference Paper · Jun 2015
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    ABSTRACT: Colon cancer is one of the most common tumors in the human population. Recent studies have shown a reduced risk for colon cancer in patients given the antidepressant fluoxetine (FLX). The exact mechanism by which FLX might protect from colon cancer remains however controversial. Here, FLX reduced the development of different colon tumor xenografts, as well as proliferation in hypoxic tumor areas within them. FLX treatment also decreased microvessel numbers in tumors. Although FLX did not increase serum and tumor glucose levels as much as the colon chemotherapy goldstandard Fluorouracil did, lactate levels were significantly augmented within tumors by FLX treatment. The gene expression of the MCT4 lactate transporter was significantly downregulated. Total protein amounts from the third and fifth mitochondrial complexes were significantly decreased by FLX in tumors. Cell culture experiments revealed that FLX reduced the mitochondrial membrane potential significantly and disabled the reactive oxygen species production of the third mitochondrial complex. Furthermore, FLX arrested hypoxic colon tumor cells in the G0/G1 phase of the cell-cycle. The expression of key cell-cycle-related checkpoint proteins was enhanced in cell culture and in vivo experiments. Therefore, we suggest FLX impairs energy generation, cell cycle progression and proliferation in tumor cells, especially under condition of hypoxia. This then leads to reduced microvessel formation and tumor shrinkage in xenograft models. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · May 2015 · Cellular Signalling
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    ABSTRACT: Degeneration of basal forebrain (BF) cholinergic nuclei is associated with cognitive decline, and this effect is believed to be mediated by neuronal dysfunction in the denervated cortical areas. MRI-based measurements of BF atrophy are increasingly being used as in vivo surrogate markers for cholinergic degeneration, but the functional implications of reductions in BF volume are not well understood. We used high-resolution MRI, fluorodeoxyglucose-positron emission tomography (PET), and neuropsychological test data of 132 subjects with mild cognitive impairment (MCI) and 177 cognitively normal controls to determine associations between BF atrophy, cortical hypometabolism, and cognitive deficits. BF atrophy in MCI correlated with both impaired memory function and attentional control deficits, whereas hippocampus volume was more specifically associated with memory deficits. BF atrophy was also associated with widespread cortical hypometabolism, and path analytic models indicated that hypometabolism in domain-specific cortical networks mediated the association between BF volume and cognitive dysfunction. The presence of cortical amyloid pathology, as assessed using AV45-PET, did not significantly interact with the observed associations. These data underline the potential of multimodal imaging markers to study structure-function-cognition relationships in the living human brain and provide important in vivo evidence for an involvement of the human BF in cortical activity and cognitive function.
    No preview · Article · Apr 2015 · Cerebral Cortex
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    ABSTRACT: The hippocampus is one of the most essential components of the human brain and plays an important role in learning and memory. The hippocampus has drawn great attention from scientists and clinicians due to its clinical importance in diseases such as Alzheimer's disease (AD), non-AD dementia, and epilepsy.. Understanding the function of the hippocampus and related disease mechanisms requires comprehensive knowledge of the orchestration of the genome, epigenome, transcriptome, proteome, and post-translational modifications (PTMs) of proteins. The past decade has seen remarkable advances in the high-throughput sequencing techniques that are collectively called next generation sequencing (NGS). NGS enables the precise analysis of gene expression profiles in cells and tissues, allowing powerful and more feasible integration of expression data from the gene level to the protein level, even allowing "-omic" level assessment of PTMs. In addition, improved bioinformatics algorithms coupled with NGS technology are finally opening a new era for scientists to discover previously unidentified and elusive proteins. In the present review, we will focus mainly on the proteomics of the human hippocampus with an emphasis on the integrated analysis of genomics, epigenomics, transcriptomics, and proteomics. Finally, we will discuss our perspectives on the potential and future of proteomics in the field of hippocampal biology. This article is part of a Special Issue entitled: Neuroproteomics: Applications in Neuroscience and Neurology. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Mar 2015 · Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics
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    ABSTRACT: Pharmacological interventions in Alzheimer's disease (AD) are likely to be more efficacious if administered early in the course of the disease, foregoing the spread of irreversible changes in the brain. Research findings underline an early vulnerability of the isodendritic core (IC) network to AD neurofibrillary lesions. The IC constitutes a phylogenetically conserved subcortical system including the locus coeruleus in pons, dorsal raphe nucleus, and substantia nigra in the midbrain, and nucleus basalis of Meynert in basal forebrain. Through their ascending projections to the cortex, the IC neurons regulate homeostasis and behavior by synthesizing aminergic and cholinergic neurotransmitters. Here we reviewed the evidence demonstrating that neurons of the IC system show neurofibrillary tangles in the earliest stages of AD, prior to cortical pathology, and how this involvement may explain pre-amnestic symptoms, including depression, agitation, and sleep disturbances in AD patients. In fact, clinical and animal studies show a significant reduction of AD cognitive and behavioral symptoms following replenishment of neurotransmitters associated with the IC network. Therefore, the IC network represents a unique candidate for viable therapeutic intervention and should become a high priority for research in AD.
    No preview · Article · Feb 2015 · Journal of Alzheimer's disease: JAD
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    ABSTRACT: The role of neuroinflammation in the pathogenesis of neurodegenerative diseases has become more evident in recent years. Research on the etiology and pathogenesis of sporadic Alzheimer's disease (AD) has focused on the role of chemokines such as CX3CL1, on the triggering receptors expressed by myeloid cells (TREMs), especially TREM2, and on the transcription factor/nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARγ). Here we analyzed the expression levels of CX3CL1, TREM2, and PPARγ in tissue homogenates from human brain regions that have different degrees of vulnerability to neuropathological AD-related changes to obtain insights into the pathogenesis and progression of AD. We found that CX3CL1 and TREM2, two genes related to neuroinflammation, are more highly expressed in brain regions with pronounced vulnerability to AD-related changes, such as the hippocampus, and that the expression levels reflect the course of the disease, whereas regions with low vulnerability to AD, seemed generally less affected by neuroinflammation. Furthermore, our results support previous findings of significantly higher CX3CL1 plasma levels in patients with mild to moderate AD than in patients with severe AD. Thus, CX3CL1 should be considered as promising additional marker for the early diagnosis of AD and underlines once more, the involvement of the neuroinflammation in the pathogenesis of this neurodegenerative disease.
    Full-text · Article · Jan 2015 · Journal of Neural Transmission
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    ABSTRACT: The fornix and hippocampus are critical to recollection in the healthy human brain. Fornix degeneration is a feature of aging and Alzheimer's disease. In the presence of fornix damage in mild cognitive impairment (MCI), a recognized prodrome of Alzheimer's disease, recall shows greater dependence on other tracts, notably the parahippocampal cingulum (PHC). The current aims were to determine whether this shift is adaptive and to probe its relationship to cholinergic signaling, which is also compromised in Alzheimer's disease. Twenty-five human participants with MCI and 20 matched healthy volunteers underwent diffusion MRI, behavioral assessment, and volumetric measurement of the basal forebrain. In a regression model for recall, there was a significant group × fornix interaction, indicating that the association between recall and fornix structure was weaker in patients. The opposite trend was present for the left PHC. To further investigate this pattern, two regression models were generated to account for recall performance: one based on fornix microstructure and the other on both fornix and left PHC. The realignment to PHC was positively correlated with free recall but not non-memory measures, implying a reconfiguration that is beneficial to residual memory. There was a positive relationship between realignment to PHC and basal forebrain gray matter volume despite this region demonstrating atrophy at a group level, i.e., the cognitive realignment to left PHC was most apparent when cholinergic areas were relatively spared. Therefore, cholinergic systems appear to enable adaptation to injury even as they degenerate, which has implications for functional restoration. Copyright © 2015 Ray et al.
    No preview · Article · Jan 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: The stabilization of the images of objects of the visual world onto the central foveal region of the retina enables a clear and stable view of our environment which is achieved by seven different types of eye movements (Table 6.1) (Leigh and Kennard 2004; Leigh and Zee 2006; Rüb et al. 2008b, 2009). The principal aim of these different types of eye movements is either to stabilize gaze to hold images steadily on the central foveal region of the retina or to shift gaze and bring images of objects of the visual world to the retina’s fovea independent of head movements. The eye movements are generated by distinct and widely separated oculomotor circuits, which involve a variety of premotor oculomotor brainstem nuclei and converge at the level of the cranial nerve nuclei concerned with eye movements (i.e., oculomotor, trochlear, and abducens nuclei). The oculomotor functions are traditionally subdivided on the basis of how they aid vision: saccades, smooth pursuits, vergence, vestibulo-ocular reflex, optokinetic nystagmus, fixation, and gaze holding (Table 6.1) (Büttner and Büttner-Ennever 2006; Büttner-Ennever and Horn 1997; Leigh and Kennard 2004; Leigh and Zee 2006; Rüb et al. 2008b, 2009).
    No preview · Chapter · Jan 2015
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    ABSTRACT: Neurons are extremely polarized cells with a complex and unique morphology, as well as long processes (axon and dendrites) that extend far away from the nerve cell body. This architectonic feature of polarization with afferent (i.e., dendrites) and efferent processes (i.e., axons) requires efficient communication between the body of nerve cells and their periphery and makes nerve cells particularly dependent on functionally intact, sufficient, and timely axonal and/or dendritic intracellular transport processes over long distances. These intra-axonal trafficking processes guarantee bidirectional transport of subcellular compartments, including membrane organelles to or from the nerve cell processes, and enable the supply for specific action sites in the axon (e.g., nodes of Ranvier, axon terminal, synapses) and the disposal of vital cell organelles, membrane structures, synaptic vesicles, soluble neuronal proteins, or ion channels. Therefore, these targeted intraneuronal transport processes represent an essential prerequisite for the survival of the nerve cells of the human brain. The functional maintenance of nerve cells depends largely on the sufficient, locally correct, and precisely timed anterograde axonal transport of proteins and cell organelles from the cell body. In addition, the proper nerve cell function requires the retrograde trafficking of worn-out cell organelles back from the terminal regions to the cell body (Fig. 8.1) (De Vos et al. 2008; Gunawardena and Goldstein 2005; Li and Conforti 2013; Millecamps and Julien 2013). Long-range microtubule-based transport of cargos is the main mechanism (1) to deliver and target cellular components, organelles, and proteins from the cell body to their peripheral action site and/or (2) to remove them in the case of exhaustion. This long-range microtubule-based transport is accomplished by two major components: (1) “engines” or main microtubule-based molecular motors (i.e., kinesin, dynein) which need energy from ATP hydrolysis to move cargos along the microtubule cytoskeletal tracks and (2) neuronal microtubules, which represent the “rails” on which molecular motors loaded with cargos can run. Microtubules are very important in a number of cellular processes and are involved in maintaining the structure of the cell and, together with microfilaments and intermediate filaments as well as microtubules, form the cytoskeleton within the nerve cell’s cytoplasm. Neuronal microtubules are long, hollow cylinders made up of polymerized α- and β-tubulin dimers, are among the core structures of the neuronal cytoskeleton, and are crucial for the maintenance of its structure as well as for organizing motility and transport of intracellular constituents. Microtubule-associated proteins (MAP) like the cytoskeletal protein tau bind to and stabilize neuronal microtubules, promote their correct polymerization and assembly, and maintain their structural integrity. Neuronal microtubules are highly dynamic structures capable to undergo rapid periods of growth and shrinkage to generate force and enable the motor proteins kinesin and dynein to transport neuronal organelles and other cellular components, as well as neuronal proteins (Fig. 8.1) (De Vos et al. 2008; Gunawardena and Goldstein 2005; Li and Conforti 2013; Millecamps and Julien 2013).
    No preview · Chapter · Jan 2015

Publication Stats

4k Citations
916.54 Total Impact Points

Institutions

  • 2015
    • Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
      San Paulo, São Paulo, Brazil
    • University of São Paulo
      San Paulo, São Paulo, Brazil
  • 1988-2015
    • University of Wuerzburg
      • • Department of Psychiatry, Psychosomatics, and Psychotherapy
      • • Institute for Forensic Medicine
      Würzburg, Bavaria, Germany
  • 1983-1984
    • RWTH Aachen University
      Aachen, North Rhine-Westphalia, Germany