Synucleinopathies comprise a diverse group of neurodegenerative proteinopathies that share common pathological lesions composed of aggregates of conformational and posttranslational modifications of alpha-synuclein in selected populations of neurons and glia. Abnormal filamentous aggregates of misfolded alpha-synuclein protein are the major components of Lewy bodies, dystrophic (Lewy) neurites, and the Papp-Lantos filaments in oligodendroglia and neurons in multiple system atrophy linked to degeneration of affected brain regions. The synucleinopathies include (1) Lewy body disorders and dementia with Lewy bodies, (2) multiple system atrophy (MSA), and (3) Hallervorden-Spatz disease. (1) The pathological diagnosis of Lewy body disorders and dementia with Lewy bodies is established by validated consensus criteria based on semiquantitative assessment of subcortical and cortical Lewy bodies as their common hallmarks. They are accompanied by subcortical multisystem degeneration with neuronal loss and gliosis with or without Alzheimer pathologic state. Lewy bodies also occur in numerous other disorders, including pure autonomic failure, neuroaxonal dystrophies, and various amyloidoses and tauopathies. (2) Multiple system atrophy, a sporadic, adult-onset degenerative movement disorder of unknown cause, is characterized by alpha-synuclein-positive glial cytoplasmic and rare neuronal inclusions throughout the central nervous system associated with striatonigral degeneration, olivopontocerebellar atrophy, and involvement of medullar and spinal autonomic nuclei. (3) In neurodegeneration with brain iron accumulation type I, or Hallervorden-Spatz disease, alpha-synuclein is present in axonal spheroids and glial and neuronal inclusions. While the identity of the major components of Lewy bodies suggests that a pathway leading from normal soluble to abnormal misfolded filamentous proteins is central for their pathogenesis, regardless of the primary disorder, there are conformational differences in alpha-synuclein between neuronal and glial aggregates, showing nonuniform mapping for its epitopes. Despite several cellular and transgenic models, it is not clear whether inclusion body formation is an adaptive/neuroprotective or a pathogenic reaction/process generated in response to different, mostly undetermined, functional triggers linked to neurodegeneration.

Neurofibrillary tangle predominant dementia (NFTPD) is a subset of late onset dementia, clinically different from traditional "plaque and tangle" Alzheimer disease (AD): later onset, shorter duration, less severe cognitive impairment, and almost absence of ApoE epsilon4. Neuropathology reveals abundant allocortical neurofibrillary pathology with no or few isocortical tau lesions, absence of neuritic plaques, absence or scarcity of amyloid deposits, but neurofibrillary changes comprising both 3 and 4 repeat (3R and 4R) tau immunohistochemistry are not significantly different from those in classical AD. Comparing 51 autopsy cases of NFTPD with 244 classical AD subjects, the nosology of NFTPD and its differences from AD are discussed.

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Dementia with grains, also referred to as argyrophilic grain disease, is a morphological condition in elderly individuals histologically characterised by the widespread occurrence of minute, spindle or comma‐shaped argyrophilic, tau‐immunoreactive structures distinct from neuropil threads that are predominantly located in the hippocampus and related limbic areas including the amygdala. They are suggested to arise mainly in dendrites of neurons showing accumulation of hyperphosphorylated tau proteins (pretangle stage) but not necessarily forming paired helical filaments. Argyrophilic grains are associated with argyrophilic, tau‐positive oligodendroglial inclusions (“coiled bodies”) in the white matter, while astroglia are not affected. Argyrophilic grain disease is considered to be a progressive disorder that may or may not be associated with dementia, the grains occasionally being the only morphologic substrates of cognitive decline. They often occur in combination with neuritic Alzheimer‐type lesions (many corresponding to “limbic” Braak stages III and IV) or other neurodegenerative disorders, such as progressive supranuclear palsy, corticobasal degeneration, or Pick's disease. The prevalence and pathogenesis of this condition, its clinicopathologic correlations and nosological position among tau‐pathology related disorders await further elucidation.

Summary. Progressive cell loss in specific neuronal populations is the pathological hallmark of neurodegenerative diseases , but its mechanisms remain unresolved. Apoptotic cell death has been implicated as a major mechanism in Alzheimer disease (AD), Parkinson disease (PD) and other neurodegenerative disorders. However, DNA fragmentation in human brain as a sign of neuronal cell injury is too frequent to account for the continuous loss in these slowly progressive disea ses. In a series of autopsy confirmed cases of AD, PD , related disorders, and age-matched controls, DNA fragmentation using the TUNEL method, an array of apoptosis-related proteins (ARP), proto-oncogenes, and activated caspase-3, the key enzyme of late-stage apoptosis, were examined. In AD, a considerable number of hippocampal neurons and glial cells showed DNA fragmentation with a 3-to 6-fold increase related to neurofibrillary tangles and amyloid deposits, but only 1 in 2.600 to 5.600 neurons displayed apoptotic morphology and cytoplasmic immunoreactivity for activated caspase-3, whereas no neurons were labeled in agematched controls. caspase-3 immunoreactivity was seen in granules of cells with granulovacuolar degeneration, in around 25% co-localized with early cytoplasmic deposition of tau-protein. In progressive supranuclear palsy, only single neurons and several oligodendrocytes in brainstem, some with taudeposits, were TUNEL-positive and expressed both ARPs and activated caspase-3. In PD , dementia with Lewy bodies, multisystem atrophy (MSA), and corticobasal degeneration, TUNEL-positivity and expression of ARPs or activated caspase-3 were only seen in microglia and oligodendrocytes with cytoplasmic inclusions , but not in neurons. These data pro vide evidence for extremely rare apoptotic neuronal death in AD and PSP compatible with the progression of neuronal degeneration in these chronic disease s. Apoptosis mainly involves reactive microglia and oligodendroglia, the latter often involved by deposits of insoluble fibrillary proteins, while alternative mechanisms of neuronal death may occur . Susceptible cell populations in a proapoptotic environment show increased vulnerability towards metabolic or other noxious factors , with autophagy as a possible protective mechanism in early stages of programmed cell death. The intracellular cascade leading to cell death still awaits elucidation.

Although the aetiology of Parkinson's disease (PD) and related neurodegenerative disorders is still unknown, recent evidence from human and experimental animal models suggests that a misregulation of iron metabolism, iron-induced oxidative stress and free radical formation are major pathogenic factors. These factors trigger a cascade of deleterious events leading to neuronal death and the ensuing biochemical disturbances of clinical relevance. A review of the available data in PD provides the following evidence in support of this hypothesis: (i) an increase of iron in the brain, which in PD selectively involves neuromelanin in substantia nigra (SN) neurons; (ii) decreased availability of glutathione (GSH) and other antioxidant substances; (iii) increase of lipid peroxidation products and reactive oxygen (O2)species (ROS); and (iv) impaired mitochondrial electron transport mechanisms. Most of these changes appear to be closely related to interactions between iron and neuromelanin, which result in accumulation of iron and a continuous production of cytotoxic species leading to neuronal death. Some of these findings have been reproduced in animal models using 6-hydroxydopamine, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), iron loading and beta-carbolines, although none of them is an accurate model for PD in humans. Although it is not clear whether iron accumulation and oxidative stress are the initial events causing cell death or consequences of the disease process, therapeutic efforts aimed at preventing or at least delaying disease progression by reducing the overload of iron and generation of ROS may be beneficial in PD and related neurodegenerative disorders. Current pharmacotherapy of PD, in addition to symptomatic levodopa treatment, includes 'neuroprotective' strategies with dopamine agonists, monoamine oxidase-B inhibitors (MAO-B), glutamate antagonists, catechol O-methyltransferase inhibitors and other antioxidants or free radical scavengers. In the future, these agents could be used in combination with, or partly replaced by, iron chelators and lazaroids that prevent iron-induced generation of deleterious substances. Although experimental and preclinical data suggest the therapeutic potential of these drugs, their clinical applicability will be a major challenge for future research.

Based on internal medicine and psychiatry and in close connection with pathology, the neurosciences in Austria began to develop in the 18(th) century, e.g. with the description of inflammation of the central nervous system by J. P. Franck (1745-1823) and the "phrenology" by F. J. Gall (1745-1823). Under the influence of the great pathologist C. Rokitansky (1804-1878), the tripode of the Vienna neurology - L. Türck (1810-1868), as initiator, Th. v. Meynert (1833-1892) the activator, and H. Obersteiner (1847-1922) as the founder of the Vienna Neurological Institute, presented basic contributions to the morphology and pathology of the nervous system. At the end of the 19(th) and in the early 20(th) century, they were followed by important publications by S. Fred (aphasia), C. Redlich (tabes dorsalis), F. Sträussler (CNS syphilis), A. Spitzer (fiber anatomy of the brain), P. Schilder (diffuse sclerosis), R. Barany (Nobel price for physiology and medicine 1914), J. Wagner v. Jauregg (Nobel price for medicine, 1927), O. Loewi (Nobel Price for Physiology and Medicine together with Sir H. Dale, 1936), A. Schüller (histiocytosis X), C. v. Economo (encephalitis lethargica and cytoarchitectonics of the human cerebral cortex), E. Pollak (Wilson disease), E. Gamper (mesencephalic subject), J. Gerstmann (Gerstmann-Sträussler-Scheinker syndrome and Gerstmann parietal syndrome), H. Hoff with L. Schönbauer (brain tumors and surgery), and others. Major research institutions were the departments of psychiatry I and II at the University of Vienna School of Medicine (foundation 1870), unification 1911, separation into departments of neurology, psychiatry and neuropsychiatry of children and adolescents in 1971), the Obersteiner Institute in Vienna (foundation 1882, separation 1993), the university departments at Graz and Innsbruck, both founded in 1891, and other laboratories, where renouned clinicans and neuroscientists, like O. Marburg, H. Hoff, O. Pötzl, O. Kauders, F. Seitelberger, H. Tschabitscher, K. Weingarten, H. Reisner,W. Birkmayer, H. Petsche, F. Gerstenbrand, H. Bernheimer, H. W. Heiss, H. Lassmann, W. Poewe, L. Deecke, and many of their associates produced important contributions to wide areas of modern neurosciences. Important for the future are the foundation of the Institute of Brain Research at Vienna Medical University and of the Austrian Society of Neurology which will give further impact for the future progress of neuroscience research in Austria and its integration into the international science community.

A recent clinico-pathological study of seven cases of multiple system atrophy (MSA), in addition to characteristic morphology findings, revealed unusual tau-positive cytoplasmic inclusions in astroglia, predominantly in the putamen, internal capsule and pontine basis. These lesions were particularly prominent in a woman aged 72 years who died 9 years after the onset of parkinsonism and ataxia. 1 The detection of tau-positive granules not co-localized with a-synuclein (aSyn)-positive glial cytoplasmic inclusions (GCI) in oligodendroglia, with more common expression of 4-repeat (R) than 3R tau, and related to the severity of neurodegeneration in MSA, suggested that tau may be related to a neurodegenerative pathway different from that induced by aSyn. These data could not be generally confirmed by a personal study of 44 autopsy-confirmed cases of MSA -24 MSA-P and 20 MSA-C aged 51-72 (mean 61.0) years. Histological examination using routine stains and immunohistochemistry for phosporylated tau (antibody AT 8, Innogenetics, Ghent, Belgium) and aSyn (rabbit polyclonal antibody, Chemicon, Temecula, CA, USA), was performed in all cases. 2 In a single case of MSA-P, a man aged 67 years with 7 years duration of parkinsonism without cerebellar or gait disorders, in addition to striatonigral degeneration grade III without signs of olivopontocerebellar atrophy, 3 tau-positive granules were detected in the cytoplasm of astroglia in the moderately degenerated putamen. These granules were AT8 immunoreactive and showed both RD3 and RD4 (repeat tau) immunopositivity, 4R tau being more common. These tau-positive cytoplasmic granules were observed only in proliferated astroglia, but not in oligodendroglia frequently involved by aSyn-positive GCIs. Tau-positive granules were not co-localized with GCIs and double-immunostaining showed no coexpression of tau and aSyn. The tau-positive glial granules were restricted to putamen, and neither similar glial inclusions nor any AT-8-positive Alzheimer's disease (AD)-like lesions, for example, neurofibrillary tangles, neuropil threads, or argyrophilic grains, were detected in any of the examined brain areas.No tau-positive glial granules were observed in any of the other 43 MSA cases, although AD-related lesions in allo-or neocortex were present in six cases of MSA aged 54-82 (mean 68) years. The pathogenic impact of tau accumulation in astroglial cytoplasm, which appears to be different from both GCIs and other glial lesions observed in various tauopathies, for example, progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) is poorly understood. However, recent studies showed increased accumulation of phosphorylated tau protein in the striata of Parkinson's disease (PD) patients related to increased phosphorylated glycogen-synthase kinase-3b (GSK-3b), 4 a major kinase that hyperphosphorylates tau to produce pathological forms of tau. 5 Tau in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin models and in human post mortem PD striata is hyperphosphorylated at the same sites (Ser 2...