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Astrocytic alpha-synuclein-immunoreactive inclusions have recently been noted to develop in sporadic Parkinson's disease (PD). Here, the presence of immunoreactive astrocytes is reported in 14 autopsy cases with clinically diagnosed PD and a neuropathological stage of 4 or higher. The labeled astrocytes occur preferentially in prosencephalic regions (amygdala, thalamus, septum, striatum, claustrum, and cerebral cortex). They appear first in layers V-VI of the temporal mesocortex, then in the striatum and in thalamic nuclei that project to the cortex. The topographical distribution pattern of these astrocytes closely parallels that of the cortical intraneuronal Lewy neurites and Lewy bodies, which, from their foothold in the mesocortex, gradually encroach upon neocortical association areas and even the primary fields. Thus, labeling of astrocytes appears to accompany the formation of neuronal inclusion bodies. Relatively small immunoreactive cortical pyramidal neurons in layers V-VI probably project to nearby destinations, such as the striatum and thalamus. Inasmuch as the projection neurons of both the striatum and the dorsal thalamus do not develop Lewy bodies, it is suggested that the most likely cause of the astrocytic reaction may be a slightly altered alpha-synuclein molecule that escapes from terminal axons of affected cortico-striatal or cortico-thalamic neurons and is taken up by astrocytes. Other aggregated proteins known to co-occur with PD-associated intraneuronal lesions, e.g., Abeta protein or neurofibrillary changes of the Alzheimer type, do not appear to influence the development of the alpha-synuclein immunoreactive astrocytes.

Clinical signs frequently recognized in early phases of sporadic Parkinson's disease (PD) may include autonomic dysfunctions and the experience of pain. Early disease-related lesions that may account for these symptoms are presently unknown or incompletely known. In this study, immunocytochemistry for alpha-synuclein was used to investigate the first relay stations of the pain system as well as parasympathetic and sympathetic pre- and postganglionic nerve cells in the lower brainstem, spinal cord, and coeliac ganglion in 100 microm polyethylene glycol embedded sections from six autopsy individuals, whose brains were staged for PD-associated synucleinopathy. Immunoreactive inclusions were found for the first time in spinal cord lamina I neurons. Lower portions of the spinal cord downwards of the fourth thoracic segment appeared to be predominantly affected, whereas the spinal trigeminal nucleus was virtually intact. Additional involvement was seen in parasympathetic preganglionic projection neurons of the vagal nerve, in sympathetic preganglionic neurons of the spinal cord, and in postganglionic neurons of the coeliac ganglion. The known interconnectivities between all of these components offer a possible explanation for their particular vulnerability. Lamina I neurons (pain system) directly project upon sympathetic relay centers, and these, in turn, exert influence on the parasympathetic regulation of the enteric nervous system. This constellation indicates that physical contacts between vulnerable regions play a key role in the pathogenesis of PD.

The synucleinopathy known as sporadic Parkinson's disease (PD) is a multisystem disorder that severely damages predisposed nerve cell types in circumscribed regions of the human nervous system. A recent staging procedure for the inclusion body pathology associated with PD proposes that, in the brain, the pathological process (formation of proteinaceous intraneuronal Lewy bodies and Lewy neurites) begins at two sites and continues in a topographically predictable sequence in six stages, during which components of the olfactory, autonomic, limbic, and somatomotor systems become progressively involved. In stages 1 to 2, the Lewy body pathology is confined to the medulla oblongata/pontine tegmentum and anterior olfactory structures. In stages 3 to 4, the substantia nigra and other nuclei of the basal mid- and forebrain become the focus of initially subtle and, then, severe changes. During this phase, the illness probably becomes clinically manifest. In the final stages 5 to 6, the lesions appear in the neocortex. This cross-sectional study originally was performed on 168 autopsy cases using material from 69 incidental cases and 41 clinically diagnosed PD patients as well as 58 age- and gender-matched controls. Here, the staging hypothesis is critically reconsidered and discussed., (Copyright 2006 Movement Disorder Society.)

Recently, the relationship between cognitive status and the neuropathological stages of a newly proposed staging procedure for Parkinson's disease (PD) was assessed in a cohort of 88 individuals. None of the patients had received the clinical diagnosis of dementia with Lewy bodies. The topographic distribution pattern of the cerebral Lewy body pathology was evaluated semiquantitatively in alpha-synuclein immunoreactions. MMSE scores from the last neurological examination prior to death were used to determine cognitive status and the degree of cognitive decline. Four subgroups of Mini-Mental State Examination (MMSE) scores ranging from nonsignificantly impaired to severely impaired cognition were analyzed statistically with nonparametric tests. Each of the 88 cases could be assigned to one of the PD stages 3-6, and MMSE scores correlated significantly with the aforementioned stages. Since the median MMSE scores decreased from stages 3-6, it is probable that the risk of developing dementia in PD becomes greater as the disease process in the brain progresses.

Assessment of Alzheimer's disease (AD)-related neurofibrillary pathology requires a procedure that permits a sufficient differentiation between initial, intermediate, and late stages. The gradual deposition of a hyperphosphorylated tau protein within select neuronal types in specific nuclei or areas is central to the disease process. The staging of AD-related neurofibrillary pathology originally described in 1991 was performed on unconventionally thick sections (100 mum) using a modern silver technique and reflected the progress of the disease process based chiefly on the topographic expansion of the lesions. To better meet the demands of routine laboratories this procedure is revised here by adapting tissue selection and processing to the needs of paraffin-embedded sections (5-15 mum) and by introducing a robust immunoreaction (AT8) for hyperphosphorylated tau protein that can be processed on an automated basis. It is anticipated that this revised methodological protocol will enable a more uniform application of the staging procedure.

The progressive degenerative process associated with sporadic Parkinson's disease (sPD) is characterized by formation of alpha-synuclein-containing inclusion bodies in a few types of projection neurons in both the enteric and central nervous systems (ENS and CNS). In the brain, the process apparently begins in the brainstem (dorsal motor nucleus of the vagal nerve) and advances through susceptible regions of the basal mid-and forebrain until it reaches the cerebral cortex. Anatomically, all of the vulnerable brain regions are closely interconnected. Whether the pathological process begins in the brain or elsewhere in the nervous system, however, is still unknown. We therefore used immunocytochemisty to investigate the gastric myenteric and submucosal plexuses in 150 microm cryosections and 8 microm paraffin sections from five autopsy individuals, whose brains were also staged for Parkinson-associated synucleinopathy. alpha-synuclein immunoreactive inclusions were found in neurons of the submucosal Meissner plexus, whose axons project into the gastric mucosa and terminate in direct proximity to fundic glands. These elements could provide the first link in an uninterrupted series of susceptible neurons that extend from the enteric to the central nervous system. The existence of such an unbroken neuronal chain lends support to the hypothesis that a putative environmental pathogen capable of passing the gastric epithelial lining might induce alpha-synuclein misfolding and aggregation in specific cell types of the submucosal plexus and reach the brain via a consecutive series of projection neurons.

The deposition of amyloid beta protein (Abeta) in the human brain and the generation of neurofibrillary tangles are the histopathological hallmarks of Alzheimer's disease. Accumulation of Abeta takes place in senile plaques and in cerebrovascular deposits as a result of an imbalance between Abeta production and clearance. This Review describes the different types of Abeta deposits, which can be distinguished by their morphology and by the hierarchical involvement of distinct areas of the brain in Abeta deposition. The role of intracellular Abeta in Abeta deposition and the mechanism of Abeta toxicity are also discussed.

Previous studies investigating the association between apolipoprotein E (APOE) genotypes and Parkinson disease (PD) have yielded conflicting results, and only a few have addressed APOE as a possible determinant of PD pathology. Therefore, we aimed to evaluate the relationship between APOE and PD as well as APOE and PD pathology. We studied 108 pathologically verified patients with PD and 108 controls pair-matched for age and gender. Allele frequencies of APOE differed between patients with PD and controls (p = 0.02). The frequency of epsilon4 allele increased (p = 0.01), whereas that of epsilon3 allele decreased with advancing PD pathology (p = 0.002). Only age of PD onset was an independent predictor for the rate of progression of PD pathology in which late-onset patients appeared to reach end point PD pathology more rapidly than early-onset patients (p = 0.001). In conclusion, our findings suggest that APOE may express its effect on the risk of PD by modifying the occurrence of PD pathology, but age of PD onset seems to be the principal determinant of the progression rate of PD pathology.

Alzheimer's disease (AD) and sporadic Parkinson's disease (PD) are the most frequently occurring degenerative illnesses of the human nervous system. Both involve multiple neuronal systems, but only a few types of nerve cells are prone to develop the disease-associated intraneuronal alterations. In AD affected neurons produce neurofibrillary tangles and neuropil threads, while in PD they develop Lewy bodies and Lewy neurites. In both illnesses select types of projection cells that generate long, unmyelinated or sparsely myelinated axons are particularly susceptible. This kind of selective vulnerability induces a distinctive lesional pattern which evolves slowly over time and remains remarkably consistent across cases. In the present review, lesions developing in the cerebral cortex are described against the backdrop of the internal organisation and interconnectivities linking involved cortical areas and subcortical nuclei. In AD, six and in PD, three stages can be distinguished, reflecting the predictable manner in which the proteinaceous intraneuronal inclusions spread through the cerebral cortex. In AD stages I-II and in PD stage 4, the pathological process makes inroads into the anteromedial temporal mesocortex, entorhinal allocortex, and Ammon's horn; thereafter, in AD stages III-IV and in PD stage 5, it proceeds into the adjoining high order association areas of the basal temporal neocortex. In AD stages V-VI and in PD stage 6, the damage affects additional neocortical association areas including first order association areas and eventually extends into the primary areas of the neocortex. The gradually evolving lesional pattern in AD and PD mirrors the ground plan of the cerebral cortex. The highest densities of lesions occur in the anterior mesocortical transitional zone between allo- and neocortex. From there, the involvement diminishes by degrees and extends into both the hippocampal formation and the neocortex. The severity of the neocortical lesions decreases in inverse proportion to the trajectories of increasing cortical differentiation and hierarchical refinement.

Different types of amyloid beta-protein (Abeta)-containing plaques occur in brains of Alzheimer's disease (AD) patients. Diffuse plaques seen during early stages of AD differ from neuritic plaques in later stages both with respect to the length of the Abeta peptides and the presence of other proteins, e.g., apolipoprotein-E (apoE). Since apoE is involved in Abeta transport and clearance, and the epsilon4-allele of the apolipoprotein-E gene (APOE) is a major risk factor for sporadic AD, it is plausible to speculate that apoE plays a pathophysiological role in the initiation of Abeta deposition. To address the issue of whether binding of apoE to Abeta is involved in initial Abeta deposition, we studied the human medial temporal lobe of 60 autopsy cases encompassing the full spectrum of AD-related pathology. In temporal lobe regions, which become involved for the first time at a given stage of beta-amyloidosis, all plaques represent newly formed plaques, and these were studied with immunohistochemical methods. ApoE was present in 36 cases, and was frequently co-localized with newly formed Abeta deposits detectable with anti-Abeta(42) but not with antibodies raised against N-terminal epitopes of Abeta. In 10 additional cases, immunoreactivity against apoE was completely lacking in newly formed plaques, which, at the same time, displayed immunoreactivity against N-terminal epitopes of Abeta. The failure of N-terminal epitopes of Abeta to co-localize with apoE in newly formed plaques indicates that these deposits presumably contain apoE-Abeta complexes, in which the N-terminal epitopes of Abeta are often concealed after complexing with apoE, thus preventing subsequent binding of antibodies. Moreover, apoE-positive newly formed plaques were seen more frequently in APOE epsilon4/4 cases than in non-APOE epsilon4/4 individuals, thereby underlining the potentially crucial role of apoE for the development of Abeta deposits.

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.

Normal "healthy" aging is defined as aging without disease. Many aged people do not exhibit symptoms of disease and lead normal lives, but nonetheless display pathological changes that are characteristic of Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and/or cerebrovascular disease (CVD). These changes are restricted to distinct brain regions and might represent preclinical stages of these disorders. This Perspective discusses arguments in favor of and against the hypothesis that pathological changes related to AD, PD, DLB, and CVD in the brains of nondemented elderly people represent early stages of these diseases rather than healthy aging. We conclude that early pathological disease-related changes do indeed constitute the beginning of AD, PD, DLB, and CVD rather than normal concomitants of aging, even in the absence of any clinical symptoms. Aging is, therefore, a major risk factor for these diseases but does not necessarily lead to age-related diseases.

Thorn-shaped astrocytes (TSA) are glial fibrillary tangles that contain abnormally phosphorylated and aggregated microtubule-associated tau protein. The present study examines the prevalence of TSA in the human medial temporal lobe of 100 autopsy brains aged 42-97 years (mean age: 65 years). Serial brain sections were cut at 100 microm and stained using phosphorylation-dependent anti-tau antibodies (AT8, PHF-1, TG3, Alz-50) and silver staining methods for neurofibrillary changes and beta-amyloid deposits. TSA preferentially were distributed in periventricular, subependymal, and subpial areas of the mediobasal temporal lobe (MTL). Double-labeling with AT8 and anti-GFAP antibodies demonstrated that the abnormal tau protein was deposited in astroglial cell bodies and in proximal and distal astroglial processes. A pronounced inter-individual variation was noted in the density of AT8-positive TSA, thereby allowing distinction of mild, moderate, and severe involvement. TSA were absent in individuals younger than 60 years. A significant increase in the prevalence of TSA was noted with advancing age. In the age-range of 75-98 years TSA were found in approximately 50% of all individuals. The development of TSA was not correlated with the severity of Alzheimer-related cortical pathology. In summary, this study suggests that TSA is a distinct form of glial tau pathology that occurs with a high frequency in elderly individuals.

Sporadic Parkinson's disease involves multiple neuronal systems and results from changes developing in a few susceptible types of nerve cells. Essential for neuropathological diagnosis are alpha-synuclein-immunopositive Lewy neurites and Lewy bodies. The pathological process targets specific induction sites: lesions initially occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. Thereafter, less vulnerable nuclear grays and cortical areas gradually become affected. The disease process in the brain stem pursues an ascending course with little interindividual variation. The pathology in the anterior olfactory nucleus makes fewer incursions into related areas than that developing in the brain stem. Cortical involvement ensues, beginning with the anteromedial temporal mesocortex. From there, the neocortex succumbs, commencing with high order sensory association and prefrontal areas. First order sensory association/premotor areas and primary sensory/motor fields then follow suit. This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.

The purpose of this study was to evaluate the diagnostic efficacy of iron-oxide-enhanced MRI vs CT during arterial portography (CTAP) and intraoperative ultrasound (IOUS) in detection of liver neoplasms. Seventeen patients with malignant focal liver lesions (liver metastases, n=7), hepatocellular carcinomas (HCC, n=9), and cholangiocellular carcinoma (CCC, n=1) underwent presurgical Resovist-enhanced MRI and CTAP. Two independent observers (A and B) assessed the blinded images of unenhanced and iron-oxide-enhanced MRI vs CTAP for the presence, number, and location of the liver lesions. These results were compared lesion by lesion and segment by segment with the results of intraoperative ultrasound ( n=17) serving as the reference standard. Eighty lesions were detected by intraoperative ultrasound in 17 patients. In comparison with IOUS (lesion-by-lesion analysis) the sensitivity was 86.8% for CTAP, 65% for combined unenhanced MR imaging, and 86.8% for combined Resovist-enhanced MRI as well as 86.8% for the combination of unenhanced and Resovist-enhanced MRI. Compared with the sensitivity of combined unenhanced MRI the sensitivity of CTAP as well as the sensitivity of combined Resovist-enhanced MRI was significantly higher (p<0.05). False-positive results were much higher in CTAP as compared with combined unenhanced and SPIO-enhanced MRI. Using the segment-by-segment analysis the specificity of combined unenhanced MRI with 100% (96.7-100%) as well as combined Resovist-enhanced MRI with 100% (96.7-100%) was significantly higher (p<0.05) in comparison with the specificity of CTAP with 91.1% (83.2-96.1%). The accuracy of combined unenhanced MRI was 100% (93.2-100%), combined Resovist-enhanced MRI 100% (93.6-100%) and of CTAP 85.2% (72.9-93.4%). In the detection of focal liver lesions iron-oxide-enhanced MR imaging is superior to unenhanced MRI and similar to CTAP.

The synucleinopathy known as idiopathic Parkinson's 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.

Although argyrophilic grain disease is characterized histopathologically by tau-positive lesions known as argyrophilic grains located predominantly in limbic brain regions in the absence of other diagnostic neuropathologies, the biochemical correlates of argyrophilic grains in gray and white matter have not been reported. Thus, we analyzed insoluble (pathological) tau proteins in five argyrophilic grain disease brains in comparison with those seen in Alzheimer's disease and Pick's disease. Analyses of separately dissected gray and white matter samples from various cortical regions revealed that pathological tau in argyrophilic grain disease was confined primarily to mediotemporal neocortical gray and adjacent white matter, and also to the allocortex, amygdala, and hippocampus. The amounts of sarcosyl-insoluble tau in all five cases were substantially lower than in Alzheimer's disease and Pick's disease, but the amounts of sarcosyl-insoluble tau in white matter were higher or comparable to that detected in gray matter from the same region, which distinguishes argyrophilic grain disease from Alzheimer's disease. The banding patterns of tau isoforms in argyrophilic grain disease varied: in three cases they were similar to Alzheimer's disease, but in two other cases, 4 microtubule binding repeat (4R) tau predominated, which distinguishes argyrophilic grain disease from classical Pick's disease. The differences between these three diseases were re-enforced by the predominance of straight tau filaments from argyrophilic grain disease brains. Thus, we conclude that argyrophilic grain disease is a distinct tauopathy characterized by prominent accumulation of argyrophilic grains in limbic brain regions in association with the characteristic tau biochemical and ultrastructural profile reported here.

The substantia nigra is not the induction site in the brain of the neurodegenerative process underlying Parkinson disease (PD). Instead, the results of this semi-quantitative study of 30 autopsy cases with incidental Lewy body pathology indicate that PD in the brain commences with the formation of the very first immunoreactive Lewy neurites and Lewy bodies in non-catecholaminergic neurons of the dorsal glossopharyngeus-vagus complex, in projection neurons of the intermediate reticular zone, and in specific nerve cell types of the gain setting system (coeruleus-subcoeruleus complex, caudal raphe nuclei, gigantocellular reticular nucleus), olfactory bulb, olfactory tract, and/or anterior olfactory nucleus in the absence of nigral involvement. The topographical parcellation of the nuclear grays described here is based upon known architectonic analyses of the human brainstem and takes into consideration the pigmentation properties of a few highly susceptible nerve cell types involved in PD. In this sample and in all 58 age- and gender-matched controls, Lewy bodies and Lewy neurites do not occur in any of the known prosencephalic predilection sites (i.e. hippocampal formation, temporal mesocortex, proneocortical cingulate areas, amygdala, basal nucleus of Meynert, interstitial nucleus of the diagonal band of Broca, hypothalamic tuberomamillary nucleus).

Cerebral amyloid angiopathy (CAA) is a type of beta-amyloidosis that occurs in leptomeningeal and cortical vessels of the elderly. In a sample of 41 CAA cases including 16 Alzheimer disease (AD) cases and 28 controls, we show that 2 types of sporadic CAA exist: The first type is characterized by immunohistochemically detectable amyloid beta-protein (Abeta) in cortical capillaries, leptomeningeal and cortical arteries, arterioles, veins, and venules. It is referred to here as CAA-Type 1. The second type of CAA also exhibits immunohistochemically detectable Abeta deposits in leptomeningeal and cortical vessels, with the exception of cortical capillaries. This type is termed CAA-Type 2. In cases with CAA-Type 1, the frequency of the apolipoprotein E (ApoE) epsilon4 allele is more than 4 times greater than in CAA-Type 2 cases and in controls. CAA-Type 2 cases have a higher epsilon2 allele frequency than CAA-Type 1 cases and controls. The ratio of CAA-Type 2 to CAA-Type 1 cases does not shift significantly with respect to the severity of AD-related beta-amyloidosis, with respect to degrees of CAA-severity, or with increasing age. Therefore, CAA-Type 1 is unlikely to be the late stage of CAA-Type 2; rather, they represent 2 different entities. Since both the ApoE epsilon2 and the epsilon4 allele are known to be risk factors for CAA, we can assign the risk factor ApoE epsilon4 to a distinct morphological type of CAA. The ApoE epsilon4 allele constitutes a risk factor for CAA-Type 1 and, as such, for neuropil-associated dyshoric vascular Abeta deposition in capillaries, whereas the e2 allele does not. CAA-Type 2 is not associated with the epsilon4 allele as a risk factor but shows a higher epsilon2 allele frequency than CAA-Type 1 cases and controls in our sample.

A distinctive histopathological feature of several neurodegenerative diseases, including corticobasal degeneration, argyrophilic grain disease, progressive supranuclear palsy, and Pick's disease, are achromatic nerve cells that express small heat-shock proteins, such as alphaB-crystallin or hsp-27, and develop in specific telencephalic cortical areas and subcortical nuclei. Here, we point to the consistent presence of such cells in Parkinson's disease. In this disorder, the neurons under consideration remain immunonegative for phosphorylated neurofilaments or for ubiquitin, thus exhibiting an immunocytochemical profile different from that shown by alphaB-crystallin-positive neurons in other neurodegenerative disorders. In severe cases of Parkinson's disease, the alphaB-crystallin-positive neurons are dispersed throughout the cerebral cortex, amygdala, and ventral claustrum. In cases showing relatively mild involvement of the telecephalon, these neurons occur chiefly within the reaches of the anterior temporal and insular mesocortex. These telencephalic predilection sites are nearly identical with those of the alpha-synuclein pathology. Nevertheless, most of the telencephalic alphaB-crystallin-immunopositive neurons refrain from developing Lewy bodies and Lewy neurites and, vice versa, most of the nerve cells containing Lewy bodies do not accumulate alphaB-crystallin.

It is increasingly clear that the normal protein alpha-synuclein is in some manner closely associated with presynaptic components of select neuronal types within the adult human central nervous system (CNS) and, in addition, that in its pathologically altered state alpha-synuclein aggregates selectively in the form of filamentous inclusion bodies during certain progressive neurodegenerative disorders, such as familial and sporadic Parkinson's disease. By having the antibody AFshp raised specifically to alpha-synuclein to label Parkinson disease-specific Lewy bodies and Lewy neurites as well as synaptic boutons containing the unaltered protein, an initial attempt is made to map the overall distribution pattern and describe the staining behavior of the immunoreactive punctae in select regions of the prosencephalon. Neocortical immunolabeling is most prominent in the prodigious, but incompletely myelinated, association fields and faintest in the heavily myelinated primary motor and primary sensory fields, with the premotor and first order sensory association areas occupying an intermediate position. Of the thalamic grays evaluated, those containing powerfully myelinated fiber tracts (e.g. centrum medianum, habenular complex) show the weakest immunolabeling, whereas, less sturdily myelinated structures are highly immunoreactive. The fact that the immunostaining spectrum for normal alpha-synuclein is so broad, together with the fact that some thalamic sites actually are immunonegative leads to the following conclusions (1) alpha-synuclein, although present in the synaptic boutons of many nerve cells in the adult human CNS, is by no means ubiquitous there, and (2) neuronal types lacking the normal protein cannot generate the Parkinson's disease-specific filamentous pathology.

The deposition of Abeta protein (Abeta) and the development of neurofibrillary changes are important histopathological hallmarks of Alzheimer disease (AD). In this study, the medial temporal lobe serves as a model for the changes in the anatomical distribution pattern of different types of Abeta-deposits occurring in the course of AD, as well as for the relationship between the development of Abeta-deposition and that of neurofibrillary pathology. In the first of 4 phases of beta-amyloidosis, diffuse non-neuritic plaques are deposited in the basal temporal neocortex. The same plaque type appears in the second phase within the external entorhinal layers pre-beta and pre-gamma, and fleecy amyloid deposits occur in the internal entorhinal layers pri-alpha, pri-beta, pri-gamma, and in CA1. In the third phase, Abeta-deposits emerge in the molecular layer of the fascia dentata, and band-like Abeta-deposits occur in the subpial portion of the molecular layer of both the entorhinal region and the temporal neocortex. In addition, confluent lake-like Abeta-deposits appear in the parvopyramidal layer of the presubicular region. The fourth phase is characterized by diffuse and core-only plaques in CA4. Diffuse plaques evolve sporadically in the external entorhinal layer pre-alpha. Parallel to the evolution of beta-amyloidosis as represented by the 4 phases, neuritic plaques gradually make their appearance in the temporal neocortex, entorhinal region, CA1, the molecular layer of the fascia dentata, and CA4. A prerequisite for their development is the presence of Abeta and the presence of neurofibrillary tangles in neurons targeting the regions where neuritic plaques evolve. Each of the different types of Abeta-deposits, including neuritic plaques, plays a specific role in the distinct developmental sequence as represented by the 4 phases so that the medial temporal lobe inexorably becomes involved to an ever greater extent. The step-for-step involvement of connected anatomical subfields highlights the importance of the entorhino-hippocampal pathways for the expansion of beta-amyloidosis. The 4 phases in the evolution of beta-amyloidosis correlate significantly with the stages of the neurofibrillary pathology proposed by Braak and Braak.

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 Alzheimer's disease, argyrophilic grain disease, Pick's disease, idiopathic Parkinson syndrome, and Huntington's 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 neurodegenerative 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.

From a morphological perspective, Alzheimer's disease (AD) is primarily a degenerative disorder of the neuronal cytoskeleton involving lipofuscin-laden cortical projection neurons with long, thin, and sparsely myelinated axons. The neocortical primary fields, relatively small in extent but functionally sophisticated, exhibit an early and brief myelination cycle, whereas the much more expansive but relatively simply organized association areas undergo a late and prolonged myelination process. The greater the degree of myelination and the less intense the pigmentation, the more resistant a given projection neuron may be to oxidative stress as well as to the development of AD-related neurofibrillary changes and vice versa. The neurofibrillary pathology commences from those cortical areas that are less completely myelinated and gradually progresses to the most functionally developed cortical fields that display the highest degree of myelination, thereby reflecting a hierarchy in the susceptibility of diverse cortical areas to the evolution of the AD-associated cytoskeletal pathology.