H. Bratzke

Stages in the development of Parkinson’s disease-related pathology

The synucleinopathy, idiopathic Parkinson’s disease, is a multisystem disorder that involves only a few predisposed nerve cell types in specific regions of the human nervous system. The intracerebral formation of abnormal proteinaceous Lewy bodies and Lewy neurites begins at defined induction sites and advances in a topographically predictable sequence. As the disease progresses, components of the autonomic, limbic, and somatomotor systems become particularly badly damaged. During presymptomatic stages 1–2, inclusion body pathology is confined to the medulla oblongata/pontine tegmentum and olfactory bulb/anterior olfactory nucleus. In stages 3–4, the substantia nigra and other nuclear grays of the midbrain and forebrain become the focus of initially slight and, then, severe pathological changes. At this point, most individuals probably cross the threshold to the symptomatic phase of the illness. In the end-stages 5–6, the process enters the mature neocortex, and the disease manifests itself in all of its clinical dimensions.

Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages).

Abstract. The synucleinopathy known as idiopathic Parkinsons disease (IPD) is a multi-system disorder in the course of which only a few predisposed nerve cell types in specific regions of the human brain become progressively involved. The underlying neuropathological process (formation of proteinaceous intraneuronal inclusion bodies) intracerebrally begins in clearly defined induction sites and advances in a topographically predictable sequence. Components of the autonomic, limbic, and motor systems sustain especially heavy damage. During the presymptomatic stages 1 and 2, the IPD-related inclusion body pathology remains confined to the medulla oblongata and olfactory bulb. In stages 3 and 4, the substantia nigra and other nuclear grays of the midbrain and basal forebrain are the focus of initially subtle and, then, severe changes. The illness reaches its symptomatic phase. In end-stages 5 and 6, the pathological process encroaches upon the telencephalic cortex. IPD manifests itself in all of its dimensions, which under the influence of the supervening cortical pathology are subject to increasing complexity.

Neuropathology of Alzheimer's disease: what is new since A. Alzheimer?

Abstract Alzheimer’s disease results from severe cytoskeletal alterations in only a few neuronal types within the human central nervous system. These intraneuronal changes take the form of neurofibrillary tangles and neuropil threads. Beginning in predisposed induction sites in the allocortex, the lesions follow a predictable sequence as they engulf other territories of the cerebral cortex and a specific set of subcortical nuclei. Some components of the brain are devastated, while others remain intact until the end phase of the disease. Assessment of the location of the afflicted neurons and the severity of the lesions allows the distinction of stages in the development of the disease. The degenerative process begins with the emergence of the first lesions, at whatever age it occurs. The illness remains subclinical for years, and proceeds inexorably, gradually laying waste to higher order limbic system centers. Clinical symptoms are observed only late in the course of the disease, and their appearance is usually concurrent with the encroachment of the destructive process upon neocortical association areas. The sequence of destruction bears a striking resemblance to the inverse sequence of cortical myelination. Late myelinating areas and layers develop the disease-related changes earlier and at higher densities than those which are myelinated early. The brain of the human adult is heavily laden with intraneuronal deposits of lipofuscin and neuromelanin pigment. The average density of neuronal pigmentation in given cortical areas mirrors the density of cytoskeletal lesions that develop in the course of the disease. Pigment-laden neuronal types giving rise to a single long, thin, unmyelinated or sparsely myelinated axon are particularly prone to developing Alzheimer’s disease-related cytoskeletal changes.

Chapter 20 Neuropathological hallmarks of Alzheimer's and Parkinson's diseases

Publisher Summary Alzheimers disease and Parkinsons (Lewy body) disease, the most widespread degenerative illnesses of the human brain, involve multiple neuronal systems and are the consequences of changes in the neuronal cytoskeleton, which develop in only a few susceptible types of nerve cells. In Alzheimers disease, affected neurons produce neurofibrillary tangles and neuropil threads, while in Parkinsons disease they develop Lewy bodies and Lewy neurites. In both illnesses a specific pattern of lesions evolves slowly over time and remains remarkably consistent across cases. In Alzheimers disease, six developmental stages can be distinguished, reflecting the predictable manner in which the neurofibrillary changes spread through the telencephalic cortex. In stages I and II, the pathological process makes inroads into the transentorhinal and entorhinal regions; thereafter, in stages III and IV, it proceeds into the adjoining cortical and subcortical components of the limbic system. Eventually, in stages V and VI, the devastation engulfs association areas of the neocortex. In Parkinsons disease lesions also impair portions of the limbic system. The predilection sites include the transentorhinal and entorhinal regions, the CA2 sector of the Ammons horn, the limbic thalamic nuclei, the anterior cingulated areas, agranular insular cortex, and components of the amygdala. In addition, non-thalamic nuclei with diffuse projections to the telencephalic cortex and centres that regulate endocrine and autonomic functions exhibit severe lesions.

Evolution of Alzheimer’s disease related cortical lesions

Alzheimers disease is an immutably progressing dementing disorder. Its major pathologic hallmark is the gradual development of neurofibrillary changes in a few susceptible nerve cell types. The cortical changes do not occur inevitably with advancing age. Once the disease has begun, spontaneous recovery or remissions are not observed. The initial changes develop in poorly myelinated areas of the temporal lobe. The destructive process then follows a predictable pattern as it extends into other cortical areas. Advanced age is not a prerequisite for the evolution of the lesions. Alzheimers disease is thus an age-related, but not an age-dependent disease. The spread of the neurofibrillary changes resembles the process of cortical myelination, however in reverse order.

Histological Validation of DW-MRI Tractography in Human Postmortem Tissue

Despite several previous attempts, histological validation of diffusion-weighted magnetic resonance imaging (DW-MRI)-based tractography as true axonal fiber pathways remains difficult. In the present study, we establish a method to compare histological and tractography data precisely enough for statements on the level of single tractography pathways. To this end, we used carbocyanine dyes to trace connections in human postmortem tissue and aligned them to high-resolution DW-MRI of the same tissue processed within the diffusion tensor imaging (DTI) formalism. We provide robust definitions of sensitivity (true positives) and specificity (true negatives) for DTI tractography and characterize tractography paths in terms of receiver operating characteristics. With sensitivity and specificity rates of approximately 80%, we could show a clear correspondence between histological and inferred tracts. Furthermore, we investigated the effect of fractional anisotropy (FA) thresholds for the tractography and identified FA values between 0.02 and 0.08 as optimal in our study. Last, we validated the course of entire tractography curves to move beyond correctness determination based on pairs of single points on a tract. Thus, histological techniques, in conjunction with alignment and processing tools, may serve as an important validation method of DW-MRI on the level of inferred tractography projections between brain areas.

High-Resolution Diffusion Tensor Imaging and Tractography of the Human Optic Chiasm at 9.4 T

The optic chiasm with its complex fiber micro-structure is a challenge for diffusion tensor models and tractography methods. Likewise, it is an ideal candidate for evaluation of diffusion tensor imaging tractography approaches in resolving inter-regional connectivity because the macroscopic connectivity of the optic chiasm is well known. Here, high-resolution (156 microm in-plane) diffusion tensor imaging of the human optic chiasm was performed ex vivo at ultra-high field (9.4 T). Estimated diffusion tensors at this high resolution were able to capture complex fiber configurations such as sharp curves, and convergence and divergence of tracts, but were unable to resolve directions at sites of crossing fibers. Despite the complex microstructure of the fiber paths through the optic chiasm, all known connections could be tracked by a line propagation algorithm. However, fibers crossing from the optic nerve to the contralateral tract were heavily underrepresented, whereas ipsilateral nerve-to-tract connections, as well as tract-to-tract connections, were overrepresented, and erroneous nerve-to-nerve connections were tracked. The effects of spatial resolution and the varying degrees of partial volume averaging of complex fiber architecture on the performance of these methods could be investigated. Errors made by the tractography algorithm at high resolution were shown to increase at lower resolutions closer to those used in vivo. This study shows that increases in resolution, made possible by higher field strengths, improve the accuracy of DTI-based tractography. More generally, post-mortem investigation of fixed tissue samples with diffusion imaging at high field strengths is important in the evaluation of MR-based diffusion models and tractography algorithms.

Pathological Changes in the Parahippocampal Region in Select Non‐Alzheimer's Dementias

Abstract: The transentorhinal and entorhinal regions of the human brain extend over the ambient gyrus and anterior portions of the parahippocampal gyrus. They are important components of the limbic loop which receives its major afferents from the neocortical sensory association areas and generates powerful efferent projections both directly and via intermediary relay stations to the prefrontal cortex. The bilateral structural preservation of limbic loop components is a prerequisite for the maintenance of intact memory functions. In progressive neurodegenerative diseases, such as Alzheimers disease, argyrophilic grain disease, Picks disease, idiopathic Parkinson syndrome, and Huntingtons disease, the transentorhinal and entorhinal regions are particularly susceptible to severe pathological changes. The transentorhinal region typically registers the initial alterations and becomes the most severely involved. From this transitional region of the mesocortex, the alterations usually invade with decreasing severity both the entorhinal region and temporal proneocortex. Each type of lesion that develops in the above‐mentioned neurode‐generative disorders hampers or even interrupts data‐transport from the sensory neocortex to the prefrontal neocortex, thereby contributing to the insidious development of progressive changes in personality, cognitive decline, and, ultimately, dementia.

Histological validation of high-resolution DTI in human post mortem tissue

Diffusion tensor imaging (DTI) is amongst the simplest mathematical models available for diffusion magnetic resonance imaging, yet still by far the most used one. Despite the success of DTI as an imaging tool for white matter fibers, its anatomical underpinnings on a microstructural basis remain unclear. In this study, we used 65 myelin-stained sections of human premotor cortex to validate modeled fiber orientations and oft used microstructure-sensitive scalar measures of DTI on the level of individual voxels. We performed this validation on high spatial resolution diffusion MRI acquisitions investigating both white and gray matter. We found a very good agreement between DTI and myelin orientations with the majority of voxels showing angular differences less than 10°. The agreement was strongest in white matter, particularly in unidirectional fiber pathways. In gray matter, the agreement was good in the deeper layers highlighting radial fiber directions even at lower fractional anisotropy (FA) compared to white matter. This result has potentially important implications for tractography algorithms applied to high resolution diffusion MRI data if the aim is to move across the gray/white matter boundary. We found strong relationships between myelin microstructure and DTI-based microstructure-sensitive measures. High FA values were linked to high myelin density and a sharply tuned histological orientation profile. Conversely, high values of mean diffusivity (MD) were linked to bimodal or diffuse orientation distributions and low myelin density. At high spatial resolution, DTI-based measures can be highly sensitive to white and gray matter microstructure despite being relatively unspecific to concrete microarchitectural aspects.

Isolation and molecular characterization of brain microvascular endothelial cells from human brain tumors.

SummaryBrain tumor formation and growth is accompanied by the proliferation and infiltration of blood capillaries. The phenotypes of endothelial cells that make up capillaries are known to differ not only in the tissues in which endothelial cells are located but also as a result of the microenvironment to which they are exposed. For this reason, primary cultures of brain endothelial cells were isolated from human brain tumors removed by surgery and compared with cells from normal tissue. The primary confluent monolayers that grew out of isolated capillary fragments consisted of closely associated, elongated, fusiform-shaped cells. But brain tumor-derived endothelial cells in culture exhibited significantly less expression of endothelial-specific Factor VIII-related antigen compared with cells isolated from normal tissue. Cultured cells that exhibited binding of Ulex europaeus lectin were shown to take up Dil-Ac-Ldl and formed continuous monolayers that were joined together by tight junctions. The cells also exhibited characteristics of the cells of the brain microvasculature in vitro as seen by the presence of large numbers of mitochondria and few pinocytotic vesicles and by the absence of Weibel-Palade bodies within the cells. The expression of vascular cell adhesion molecule-1, E-Selectin, and the tight junction associated protein ZO-1 but not intercellular adhesion molecule-1 was demonstrated by immunohistological staining or reverse transcriptase-polymerase chain reaction methodologies. Comparative studies of these endothelial cells with endothelial cells from normal tissue will be useful for determining and understanding how the blood-brain barrier differs and functions in tumor and healthy tissues and may lead to strategies for brain tumor therapeutic approaches.