Alzheimer Disease: Jellinger KA

Jellinger KA. · Institute of Clinical Neurobiology, Vienna, Austria. · Front Neurol Neurosci. · Pubmed #19182469 No free full text.

Abstract: Dementia is increasingly recognized as a common feature in patients with Parkinson disease (PD)and dementia with Lewy bodies (DLB), both sharing many clinical and morphological features and believed to form a continuum within the spectrum of Lewy body diseases. Based on a large autopsy series of parkinsonism (31-37% with dementia) and review of the recent literature, the pathological changes underlying cognitive impairment in PD with dementia (PDD) and DLB are discussed. PD cases with Lewy body stages 3-5, i.e. only mild to moderate cortical alpha-synuclein (alphaSyn) depositions,and no additional pathologies, are rarely associated with cognitive impairment, which is frequently seen in PD and DLB cases with considerable cortical and limbic alphaSyn load (increasing Lewy body densities) and/or associated widespread Alzheimer-type pathology. Clinicopathological studies show a negative relation between cognitive impairment and both cortical Lewy body pathology and Alzheimer type changes, suggesting that these either alone or in combination are major causes of cognitive dysfunction, while others related them to presynaptic alphaSyn aggregates. The neuropathology of PDD and DLB is similar, without significant differences between cortical and subcortical Lewy bodies and the pattern of synuclein pathology in the brainstem, but there are topographic differences in nigral lesions, more frequent affection of the hippocampal CA 2/3 subareas and more severe diffuse amyloid plaque load in the striatum of DLB. In conclusion, the pathology underlying cognitive impairment in PDD and DLB is heterogeneous, but there are some differences in the topography and severity of lesions between both phenotypes that need further evaluation.

Jellinger KA. · Institute of Clinical Neurobiology, Kenyongasse 18, 1070, Vienna, Austria. · Acta Neuropathol. · Pubmed #19052757 No free full text.

Abstract: There are several consensus criteria for both the clinical and neuropathological diagnosis of different types of dementias. The clinical diagnostic accuracy using revised research criteria and newly developed biomarkers (MRI, PET, CSF analysis, genetic markers) ranges from 65 to 96% (for Alzheimer disease) with a specificity of diagnostic criteria versus other dementias of 23-88%. Neuropathological assessment of dementing disorders using immunohistochemistry, molecular biologic and genetic methods can achieve a diagnosis/classification, based on the homogeneous definitions, harmonized inter-laboratory methods and standards for the assessment of nervous system lesions, in about 99%, without, however, being able to clarify the causes/etiology of most of these disorders. Further prospective and concerted clinicopathological studies using revised methodological and validated protocols and uniform techniques are required to establish the nature, distribution pattern and grades of lesions and; thus, to overcome the limitations of the current diagnostic framework. By data fusion this my allow their more uniform application and correlation with the clinical data in order to approach a diagnostic "gold standard", and to create generally accepted criteria for differentiating cognitive disorders from healthy brain aging. The detection of disease-specific pathologies will be indispensable to determinate the efficacy of new therapy options.

Jellinger KA. · Institute of Clinical Neurobiology, Kenyongasse 18, 1070, Vienna, Austria. · Acta Neuropathol. · Pubmed #18592254 No free full text.

Abstract: Sporadic Parkinson disease (sPD) or brainstem-predominant type of Lewy body (LB) disease, and dementia with Lewy bodies (DLB), the two most frequent alpha-synucleinopathies, are progressive multisystem neurodegenerative disorders with widespread occurrence of alpha-synuclein (AS) deposits in the central, peripheral, and autonomic nervous system. For both LB-related disorders, staging/classification systems based on semiquantitative assessment of the distribution and progression pattern of Lewy-related/AS pathology are used that are considered to be linked to clinical dysfunctions. In PD, a six-stage system (Braak) has been suggested to indicate a predictable sequence of lesions with ascending progression from medullary and olfactory nuclei to the cortex, the first two presymptomatic stages being related to incidental LB disease, stages 3 and 4 with motor symptoms, and the last two (cortical) stages may be frequently associated with cognitive impairment. DLB, according to consensus pathologic guidelines, by semiquantitative scoring of AS pathology (LB density and distribution) in specific brain regions, is distinguished into three phenotypes (brainstem, transitional/limbic, and diffuse neocortical), also considering concomitant Alzheimer-related pathology. Retrospective clinico-pathologic studies, although largely confirming the staging system, particularly for younger onset PD with long duration, have shown that between 6.3 and 43% of the cases did not follow the proposed caudo-rostral progression pattern of AS pathology. There was sparing of medullary nuclei in 7-8.3% of clinically manifested PD cases with AS inclusions in midbrain and cortex corresponding to Braak stages 4 and 5, whereas mild parkinsonian symptoms were already observed in stages 2 and 3. There is considerable clinical and pathologic overlap between PD (with or without dementia) and DLB, corresponding to Braak LB stages 5 and 6, both frequently associated with variable Alzheimer-type pathology. Dementia often does not correlate with progressed stages of LB pathology, but may also be related to concomitant Alzheimer lesions or mixed pathologies. There is no relationship between Braak LB stage and the clinical severity of PD, and the predictive validity of this concept is doubtful, since large unselected, retrospective autopsy series in 30-55% of elderly subjects with widespread AS/Lewy-related pathology (Braak stages 5 and 6) reported no definite neuropsychiatric symptoms, suggesting considerable cerebral compensatory mechanisms. Applying the original criteria to large dementia samples, 49% of positive cases were not classifiable. Therefore, modified criteria for the categorization of Lewy-related pathology were proposed for patients with a history of dementia. The causes and molecular basis of the not infrequent deviations from the current staging schemes of AS pathology in PD and DLB, its relation to the onset of classical parkinsonian symptoms and for the lack of definite clinical deficits despite widespread AS pathology in the nervous system remain to be elucidated.

Jellinger KA. · Institute of Clinical Neurobiology, Vienna, Austria. · J Alzheimers Dis. · Pubmed #18525132 No free full text.

Abstract: The prevalence, morphology and pathogenesis of vascular dementia (VaD), recently termed vascular cognitive disorder (VCD), are a matter of discussion.VaD is suggested in 8-15% of cognitively impaired aged subjects. Its prevalence in autopsy series ranges from 0.03 to 58% (mean 8-15% in Western series, 22-35% in Japan). Neuropathology shows multifocal and/or diffuse lesions, ranging from lacunes and microinfarcts, often involving subcortical and strategically important brain areas (thalamus, frontobasal, limbic system), white matter lesions and hippocampal sclerosis to multi-infarct encephalopathy and diffuse post-ischemic lesions. They result from systemic, cardiac and local large and small vessel disease. Pathogenesis is multifactorial and pathophysiology affects neuronal networks involved in cognition, behavior, execution and memory. Vascular lesions often coexist with Alzheimer's disease (AD) and other pathologies. Minor vascular lesions hardly contribute to cognitive decline in full-blown AD, while both mild Alzheimer pathology and small vessel disease interact synergistically. AD pathology is less severe in the presence of vascular lesions. The lesion pattern in "pure" VaD/VCD) related to microangiopathies differs from that in "mixed dementia" (AD + vascular encephalopathy), often associated with large infarcts, suggesting different pathogenesis. Due to the heterogeneity of cerebrovascular pathology and its causative factors, no validated neuropathologic criteria for VaD are currently available, and a large variability across laboratories still exists in morphologic examination procedures and techniques. Further prospective clinico-pathologic studies are needed to validate diagnostic criteria for VaD and to clarify the impact of vascular lesions on cognitive impairment.

Jellinger KA. · Institute of Clinical Neurobiology, Kenyongasse 18, A 1070 Vienna, Austria. · J Neurol Sci. · Pubmed #18455191 No free full text.

Abstract: Vascular dementia/vascular cognitive impairment (VaD/VCI) is not a single entity, but a large group of conditions characterized by various clinical and morphological findings and variable pathophysiology. Clinical diagnostic criteria show moderate sensitivity (50-70%) and variable specificity (64-98%). Epidemiological studies are hampered by the lack of clear and validated diagnostic criteria, the complexity of brain pathologies, ethnic and geographic variations. In Western clinic-based series VaD/VCI is suggested in 8-15% of cognitively impaired aged subjects, with age-standardized incidence ratios 0.42-2.6 and clinical prevalence at age 70+ of 6-15/1000 person/year. Prevalence in autopsy series ranges from 0.03 to 58% (real mean 8-15% in Western series, 22-35% in Japan). Both prevalence and incidence increase with age. Neuropathology shows multifocal and/or diffuse lesions, ranging from lacunes and microinfarcts, white matter lesions, hippocampal sclerosis to multi-infarct encephalopathy, mixed cortico-subcortical and diffuse post-ischemic lesions. They result from systemic, cardiac, local large and small vessel disease. Pathogenesis is multifactorial and cognitive decline is commonly associated with small ischemic/vascular lesions, often involving subcortical and strategically important brain areas (thalamus, frontobasal, limbic system). Pathophysiology affects neuronal networks involved in cognition, behavior, execution and memory. Vascular lesions often coexist with Alzheimer disease (AD) and other lesions, multiple pathologies greatly increasing the odds of dementia; 25-80% of demented subjects show both AD and cerebrovascular lesions. While both factors by synergistic interaction contribute significantly to the risk of dementia, AD pathology is often less severe in the presence of vascular lesions. Due to the heterogeneity of cerebrovascular pathology and its causative factors, no validated neuropathologic criteria for VaD are currently available, and a large variability across laboratories still exists in morphologic examination procedures and techniques. Harmonization of neuropathologic procedures and evaluation criteria in future prospective clinico-pathologic studies are needed to validate diagnostic criteria for VaD and to clarify the impact of vascular lesions on cognition.

Jellinger KA, Janetzky B, Attems J, Kienzl E. · Institute of Clinical Neurobiology, Vienna, Austria. · J Cell Mol Med. · Pubmed #18363842 No free full text.

Abstract: Simple, non-invasive tests for an early detection of degenerative dementia by use of biomarkers are urgently required. However, up to the present, no validated extracerebral diagnostic markers (plasma/serum, platelets, urine, connective tissue) for the early diagnosis of Alzheimer disease (AD) are available. In disease stages with evident cognitive disturbances, the clinical diagnosis of probable AD is made with around 90% accuracy using modern clinical, neuropsychological and imaging methods. Diagnostic sensitivity and specificity even in early disease stages are improved by CSF markers, in particular combined tau and amyloid beta peptides (Abeta) and plasma markers (eg, Abeta-42/Abeta-40 ratio). Recently, a novel gene/protein--ALZAS (Alzheimer Associated Protein)--with a 79 amino acid sequence, containing the amyloid beta-42 fragment (Abeta-42), the amyloid precursor protein (APP) transmembrane signal and a 12 amino acid C-terminal, not present in any other known APP alleles, has been discovered on chromosome 21 within the APP region. Reverse transcriptase-PCR revealed the expression of the transcript of this protein in the cortex and hippocampal regions as well as in lymphocytes of human AD patients. The expression of ALZAS is mirrored by a specific autoimmune response in AD patients, directed against the ct-12 end of the ALZAS-peptide but not against the Abeta-sequence. ELISA studies of plasma detected highest titers of ALZAS in patients with mild cognitive impairment (presymptomatic AD), but only moderately increased titers in autopsy-confirmed AD, whereas low or undetectable ct-12 titers were found in cognitively intact age-matched subjects and young controls. The antigen, ALZAS protein, was detected in plasma in later clinical stages of AD. It is suggested that ALZAS represents an indicator in a dynamic equilibrium between both peripheral and brain degenerative changes in AD and may become a useful "non-invasive" diagnostic marker via a simple blood test.

Jellinger KA. · Institute of Clinical Neurobiology, Vienna, Austria. · Neurodegener Dis. · Pubmed #18322367 No free full text.

Abstract: BACKGROUND: Proteinopathies are a heterogenous group of neurodegenerative disorders, characterized by intra- and extracellular accumulation of abnormal filament proteins. OBJECTIVE: To describe the neuropathology of specific forms of tauopathies and synucleinopathies, the overlap of morphologic features and molecular interactions. METHODS: The study uses currently available morphologic criteria of different proteinopathies. RESULTS: Alzheimer disease (AD) is featured by deposition of beta-amyloid peptides, phosphorylated tau protein (3- and 4-repeat tau) and frequent alpha-synuclein (aSyn) deposits. Lewy body diseases (LBD), such as sporadic Parkinson disease (PD) and dementia with Lewy bodies (DLB), show aSyn-positive deposits in neurons, neurites, glia, and presynaptic terminals, while frontotemporal dementias present tau-positive and tau-negative, ubiquitin- and TDP-43-positive neuronal and glial inclusions. The latter have also been observed in AD, PD, PD dementia and motor neuron disorders. Molecular interactions between major proteins, which may occur within the same brain in various distribution patterns, cause variable phenotypes and mixed pathologies, e.g. AD with aSyn pathology in the brainstem and amygdala, PD and DLB with AD lesions, and frontotemporal dementia with a mixture of various deposits, while others are featured by one principal pathology without other lesions (e.g. tangle-predominant type of dementia, pure PD, brainstem-predominant LBD). CONCLUSION: Animal models and in vitro studies showing co-occurrence and mutual promotion of fibrillation of these proteins indicate their synergistic interactions in the pathogenesis of these disorders which, at least in part, are genetically influenced.

Jellinger KA, Attems J. · Institute of Clinical Neurobiology, 18, Kenyongasse, A-1070 Vienna, Austria. · J Neurol Sci. · Pubmed #17324442 No free full text.

Abstract: Mixed dementia (MD) refers to a combination of definite Alzheimer disease (AD) and vascular encephalopathy, but the distinction between both disorders is controversial. For the diagnosis of MD the clinical/neuroimaging criteria of possible AD plus cerebrovascular disease (CVD) as separate entities are used, but causal relations between vascular brain lesions and dementia are unclear. We proposed the combination of autopsy-proven AD with multiple vascular or ischemic lesions with about 30-50 ml of infarcted/damaged brain tissue. The population-based prevalence of MD is unknown. In retrospective and prospective autopsy studies, it ranges from 2 to 58% with reasonable means of 6-12%. In a consecutive autopsy series of 1500 demented elderly subjects, 830 of which with clinically probable AD, in Vienna, Austria, 41.5 to 52.0% showed "pure" AD, 7% atypical AD, 16-20% AD plus cerebrovascular lesions, and 9% AD plus Lewy body pathology; MD was diagnosed in 4.6 and 2.4%, and "pure" vascular dementia (VaD) in 11 and 2.0%, respectively, while 16.3/6.1% were other dementing disorders, and 1% showed no specific pathology. Like the MRC-CFAS and other studies, this indicates frequent coexistence of AD with multiple cerebrovascular lesions in cognitively impaired patients. In both AD and VaD, vascular lesions frequently involved subcortical regions (basal ganglia, thalamus, hippocampus, and white matter) or were multiple microinfarcts, whereas in MD, large/hemispheral infarcts and multiple microinfarcts were more frequent, suggesting different pathogenic mechanisms. In early/mild AD, critically located small vascular lesions may induce/promote cognitive decline, but in full-blown AD they appear of minor importance. Discussion of the major pathogenic factors inducing AD, VaD and MD suggests synergistic relations between these disorders. However, currently available morphological criteria for AD and VaD are of limited value for the diagnosis of MD and generally accepted and validated histopathological criteria for the diagnosis of VaD and MD are currently not available. Therefore, more distinct and critically evaluated clinico-pathological criteria are warranted.

Jellinger KA. · Institute of Clinical Neurobiology, Kenyongasse 18, 1070, Vienna, Austria. · Acta Neuropathol. · Pubmed #17285295 No free full text.

Abstract: The prevalence, morphology and pathogenesis of vascular dementia (VaD), recently termed vascular cognitive impairment, are a matter of discussion, and currently used clinical diagnostic criteria show moderate sensitivity (average 50%) and variable specificity (range 64-98%). In Western clinic-based series, VaD is suggested in 8-10% of cognitively impaired aged subjects. Its prevalence in autopsy series varies from 0.03 to 58%, with reasonable values of 8-15%, while in Japan it is seen in 22-35%. Neuropathologic changes associated with cognitive impairment include multifocal and/or diffuse disease and focal lesions: multi-infarct encephalopathy, white matter lesions or arteriosclerotic subcortical (leuko)encephalopathy, multilacunar state, mixed cortico-subcortical type, borderline/watershed lesions, rare granular cortical atrophy, post-ischemic encephalopathy and hippocampal sclerosis. They result from systemic, cardiac and local large or small vessel disease. Recent data indicate that cognitive decline is commonly associated with widespread small ischemic/vascular lesions (microinfarcts, lacunes) throughout the brain with predominant involvement of subcortical and functionally important brain areas. Their pathogenesis is multifactorial, and their pathophysiology affects neuronal networks involved in cognition, memory, behavior and executive functioning. Vascular lesions often coexist with Alzheimer disease (AD) and other pathologies. Minor cerebrovascular lesions, except for severe amyloid angiopathy, appear not essential for cognitive decline in full-blown AD, while both mild Alzheimer pathology and small vessel disease may interact synergistically. The lesion pattern of "pure" VaD, related to arteriosclerosis and microangiopathies, differs from that in mixed-type dementia (AD with vascular encephalopathy), more often showing large infarcts, which suggests different pathogenesis of both types of lesions. Due to the high variability of cerebrovascular pathology and its causative factors, no validated neuropathologic criteria for VaD are available, and a large variability across laboratories still exists in the procedures for morphologic examination and histology techniques.

Jellinger KA. · Institute of Clinical Neurobiology, Vienna, Austria. · J Neural Transm. · Pubmed #17039299 No free full text.

Abstract: Alzheimer disease, a progressive neurodegenerative disorder of hitherto unknown etiology leading progressively to severe incapacity and death, has become the pandemic of the 21(st) century. On World Alzheimer Day, September 21, 2006, the 100(th) anniversary of the first description of the clinical and histological findings in this disorder by A. Alzheimer, was celebrated. This retrospective review of the most important events and advances in Alzheimer research presents its early history in which only clinical and histologic signs of this peculiar disease were described. Electron microscopy, quantitative morphology and modern biochemistry emerging in the second half of the 20(th) century opened a new era in dementia research with description of the ultrastructure and biochemistry of senile plaques and neurofibrillary tangles, the major disease markers of AD. Advances in the development of clinical, neuropathological, and neuroimaging criteria, modern instruments and algorithms in the diagnosis of the disorder followed, enabling long-term studies and more exact diagnosis of AD and related disorders. Landmark studies were the development of operational criteria for the post mortem diagnosis of AD based on semiquantitative assessment and developmental patterns of its major markers. Basic research gave insight into the molecular genetics and pathophysiology of AD, and, based on the biochemical findings, new pharmacological treatment options were opened. Recently, biological and other surrogate, in particular functional neuroimaging, markers allow an early detection of presymptomatic stages of AD, their risk factors and progression which, in the future, might be prevented or at least slowed by new therapeutic approaches. Since the etiology of AD is hitherto unknown, causative therapies are still not available. The paper discusses future research needs and challenges for developing new diagnostic strategies for early and accurate detection of neurodegenerative processes leading to dementia, better epidemiologic and gender data as well as more insights into the pathogenic cascade of AD and other dementing disorders which will depend on international networks and close cooperation between clinicians, neuroscientists, caregivers, public health institutions, and individual sponsors.

Jellinger KA. · Institute of Clinical Neurobiology, Kenyongasse 18, A-1070 Vienna, Austria. · Curr Alzheimer Res. · Pubmed #17017868 No free full text.

Abstract: There are myriads of reasons and ways for a neuron to die, among which apoptosis is a specific form that is processed in two major signaling pathways, the TNF-receptor-mediated (extrinsic) and the mitochondria-based (intrinsic) cell death pathway with several avenues of crosstalk between them. The molecular key players of apoptosis, the importance of the Csp cascade via interaction with different death effector domains and the role of the effector Csp-3 driving the execution of the cell death program are reviewed. Recent data suggest that caspases converge amyloid and tau Alzheimer pathologies: beta amyloid peptide activates caspases which on turn cleave tau and via phosphorylation of tau initiate tangle pathology in both Alzheimer disease and other tauopathies. Several mediators show a bifunctional regulation of apoptosis, with both pro- and anti-apoptotic activities. The latter modify the cell death pathway due to inhibition of Csp activation or other protective mechanisms and may delay it or, via abortive apoptosis ("abortosis") lead to prolonged survival of nerve cells. While the role of apoptosis in neurodegeneration is well documented in tissue culture and transgenic animal models, in human postmortem AD brain its occurrence and role are discussed controversially. Given the short duration required for the completion of apoptosis and the chronic progressive course of neurodegeneration in Alzheimer disease and related disorders, the detection of rare neurons displaying morphological signs of apoptosis and expression of the activated key-executing enzyme Csp-3 is realistic, although there is significantly increased incidence of cells with DNA fragmentation, mainly glia, and markers for a "proapoptotic" environment in the aged human brain indicate increased susceptibility of neurons to metabolic and other noxious factors. Postmortem analysis can bridge some but not all of our knowledge gaps, but the results are still controversial, and we need a better understanding of the molecular basis and pathways that drive the yin-yang between neuronal survival and death.

Jellinger KA. · Institute of Clinical Neurobiology, Vienna, Austria. · Panminerva Med. · Pubmed #15876978 No free full text.

Abstract: The prevalence, morphology, and pathogenesis of vascular dementia (VaD), recently termed vascular cognitive impairment (VCI), and of mixed dementia (Alzheimer disease associated with vascular encephalopathy) are a matter of discussion and clinical diagnostic criteria for these disorders slow low sensitivity and variable specificity. In Western memory clinic-based series, VaD/VCI is suggested in 8-10% of cognitively impaired elderly subjects. Its prevalence in autopsy series ranges from 0.03% to 58% with reasonable values of 4-10%. It has been related to focal, multifocal or diffuse cortical and/or subcortical microinfarcts and lacunes often affecting strategically important brain areas (thalamus, frontobasal and/or limbic systems), hemispheric white matter lesions and, less often, large brain infarcts. They result from systemic, cardiac or local large or small vessel disease. The pathogenesis of cerebrovascular lesions is multifactorial and their pathophysiology affects neuronal systems involved in cognition, memory, and behavior. Vascular pathology often coexists with Alzheimer disease (AD) and other dementing disorders; 25-60% of dementia cases show both AD and vascular lesions. The lesion patterns in ''pure'' VCI with predominant multiple small (subcortical) lesions related to arteriosclerosis and microangiopathies and in mixed dementia (AD associated with vascular encephalopathy), more often showing large infarcts, suggest different pathogenesis of both types of lesions. Due to the high variability of cerebrovascular pathology and its causative factors no validated neuropathological criteria exist for VCI and mixed dementia. In very old subjects selective hippocampal sclerosis may be associated with multiple other vascular pathologies. Minor cerebrovascular lesions, except for severe amyloid angiopathy, appear not essential for cognitive decline in full-blown AD, while both mild AD-type pathology and small vessel disease may interact synergistically in ''unmasking'' or promoting dementia. AD pathology is significantly less severe in the presence of cerebrovascular lesions. Further studies are needed to validate diagnostic criteria for VaD/VCI and to clarify the impact of vascular lesions on cognitive impairment as a basis for more precise clinical diagnosis, early prevention and management.

Jellinger KA. · Institute of Clinical Neurobiology, A-1070 Vienna, Austria. · Curr Opin Neurol. · Pubmed #15542981 No free full text.

Abstract: PURPOSE OF REVIEW: The link between head injury and dementia/Alzheimer's disease is controversial. This review discusses some recent epidemiological, human autopsy and experimental studies on the relationship between traumatic head injury and dementia. RECENT FINDINGS: Recent epidemiological studies have shown that head injury is a risk factor for the development of dementia/Alzheimer's disease, whereas others have not. After experimental brain trauma the long-term accumulation of amyloid beta peptide suggests that neurodegeneration is influenced by apolipoprotein E epsilon 4, and after human brain injury both amyloid beta peptide deposition and tau pathology are seen, even in younger patients. Amyloid beta peptide levels in the cerebrospinal fluid and the overproduction of beta amyloid precursor protein in humans and animals after traumatic brain injury are increased. Repeated mild head trauma in both animals and humans accelerates amyloid beta peptide accumulation and cognitive impairment. Retrospective autopsy data support clinical studies suggesting that severe traumatic brain injury with long-lasting morphological residuals are a risk factor for the development of dementia/Alzheimer's disease. The influence of the apolipoprotein E genotype on the prognosis of traumatic brain injury is under discussion. SUMMARY: Although epidemiological studies and retrospective autopsy data provide evidence that a later cognitive decline may occur after severe traumatic brain injury, the relationship between dementia after head/brain trauma and apolipoprotein E status is still ambiguous. Both human postmortem and experimental studies showing apolipoprotein beta deposition and tau pathology after head injury support the link between traumatic brain injury and dementia, and further studies are warranted to clarify this relationship.

Jellinger KA. · Institute of Clinical Neurobiology, Vienna, Austria. · Mov Disord. · Pubmed #14502650 No free full text.

Abstract: 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.

Jellinger KA. · Institute of Clinical Neurobiology, Vienna, Austria. · J Neural Transm Suppl. · Pubmed #12946052 No free full text.

Abstract: Neurodegenerative diseases are morphologically featured by progressive cell loss in specific vulnerable neuronal populations of the central nervous system, often associated with cytoskeletal protein aggregates forming intracytoplasmic and/or intranuclear inclusions in neurons and/or glial cells. Most neurodegenerative disorders are now classified either according to the hitherto known genetic mechanisms or to the major components of their cellular protein inclusions. The major basic processes inducing neurodegeneration are considered multifactorial ones caused by genetic, environmental, and endogenous factors. They include abnormal protein dynamics with defective protein degradation and aggregation, many of them related to the ubiquitin-proteasomal system, oxidative stress and free radical formation, impaired bioenergetics and mitochondrial dysfunctions, and "neuroinflammatory" processes. These mechanisms that are usually interrelated in complex vitious circles finally leading to programmed cell death cascades are briefly discussed with reference to their pathogenetic role in many, albeit diverse neurodegenerative diseases, like Alzheimer disease, synucleinopathies, tauopathies, and polyglutamine disorders. The impact of protein inclusions on cell dysfunction, activation or prevention of cell death cascades are discussed, but the molecular basis for the underlying disease mechanisms remains to be elucidated.

Jellinger KA. · Institute of Clinical Neurobiology, Vienna, Austria. · J Neural Transm Suppl. · Pubmed #12456046 No free full text.

Abstract: Both the clinical criteria and morphologic substrates of dementia resulting from cerebrovascular disease and its relation to Alzheimer disease and other age-related brain changes are controversial. In clinical and autopsy studies in the Western world the prevalence of vascular-ischemic dementia (VID) is around 7-10%, while vascular cognitive impairment without dementia is much more frequent and the risk of poststroke dementia is increased in patients with prestroke cognitive decline. In contrast to previous suggestions that VID was largely the result of large hemispheral infarcts, according to recent studies, it is most commonly associated with widespread small ischemic or vascular lesions (microinfarcts, lacunes) throughout the CNS with predominant subcortical lesions in the basal ganglia and white matter or in strategically important brain regions (thalamus, hippocampus). The lesion pattern of rare "pure" VID, which is related to arteriolosclerotic and hypertensive microangiopathy, differs from that in mixed type dementia (Alzheimer disease and cerebrovascular lesions) that more often shows larger hemispheral infarcts. Another form of VID that is not infrequent in very old subjects is hippocampal sclerosis, a selective damage to the hippocampus that is often accompanied by multiple other cerebrovascular lesions. Both, mild Alzheimer type pathology and small vessel disease-associated subcortical vascular pathology appear to be common and may interact in causing cognitive decline, but the impact of cerebrovascular lesions on cognitive impairment and dementia needs to be further elucidated.

Jellinger KA. · Ludwig Boltzmann Institute of Clinical Neurobiology, Otto Wagner Hospital, B-Bildg, 1, Baumgartner Hoehe, A-1140 Vienna, Austria. · J Neurol Sci. · Pubmed #12417375 No free full text.

Abstract: In Western memory clinic-based series, ischemic-vascular dementia (IVD) is seen in 8-10% of cognitively impaired elderly subjects. Its prevalence in autopsy series ranges from 0.03% to 58% with reasonable values of 4-10%, while in Japan, IVD is seen in 22-35% and mixed-type dementia (MTD) (Alzheimer disease/AD+IVD) in 6-11%. In a large Viennese autopsy series, "pure" IVD was observed in 9.4% of demented elderly and in 2.9% of those clinically diagnosed as possible/probable AD MTD was observed in 3.1% and 1.3% respectively. The major morphological types of IVD are multi-infarct encephalopathy (MIE), small vessel infarct type-strategic infarct dementia (SID), subcortical arteriosclerotic leukoencephalopathy (Binswanger), multilacunar state, mixed cortico-subcortical type, granular cortical atrophy, and post-ischemic encephalopathy. In contrast to previous suggestions that IVD is mainly the result of large hemispheral infarcts or losses of over 100 ml of brain tissue, recent data indicate that cognitive decline is commonly associated with widespread small ischemic or vascular lesions (microinfarcts, lacunes) throughout the brain with predominant involvement of the basal ganglia, white matter, and hippocampus. The lesion pattern of "pure" IVD, which is related to arteriolosclerosis and hypertensive microangiopathy, differs from that in mixed-type dementia, more often showing large infarcts. Although recent studies suggest that concomitant small cerebral infarcts do not significantly influence the overall rate of cognitive decline in AD patients or may be important for mental decline in early AD, both mild AD pathology and microvascular cerebral lesions appear to be common and may interact in "unmasking" or promoting dementia.

Jellinger KA. · Ludwig Boltzmann Institute of Clinical Neurobiology, Otto Wagner Hospital, Vienna, Austria. · J Neural Transm. · Pubmed #12111471 No free full text.

Abstract: Recent epidemiological and clinico-pathologic data suggest overlaps between Alzheimer disease (AD) and cerebrovascular lesions that may magnify the effect of mild AD pathology and promote progression of cognitive decline or even may precede neuronal damage and dementia.Vascular pathology in the aging brain and in AD includes: 1. cerebral amyloid angiopathy (CAA) with an incidence of 82-98% often associated with ApoE epsilon 2 and causing a) cerebral mass hemorrhages (around 70%, mainly in the frontal and parietal lobes), b) multiple or recurrent microhemorrhages (15%), and c) ischemic (micro-)infarcts or lacunes (around 20%). The frequency of these lesions increases with the severity of CAA and shows no correlation with that of senile amyloid plaques. CAA, significantly more frequent in patients with cerebral hemorrhages or infarcts than in aged controls, is an important risk factor for cerebrovascular lesions in AD. 2. Microvascular changes with decreased density and structural abnormalities causing regional metabolic and blood-brain barrier dysfunctions with ensuing neuronal damage. In large autopsy series of demented aged subjects, around 80% show Alzheimer type pathology, 20-40% with additional, often minor vascular lesions, 7-10% "pure" vascular dementia, and 3-5% "mixed" dementia (combination of AD and vascular encephalopathy). AD cases with additional minor cerebrovascular lesions have significantly more frequent histories of hypertension or infarcts than "pure" AD patients. Vascular lesions in AD include cortical microinfarcts, subcortical lacunes, white matter lesions / leukoencephalopathy, small hemorrhages and corticosubcortical infarcts, while in mixed type dementia multiple larger or hemispheral infarcts are more frequent. Small infarcts in AD patients have no essential impact on global cognitive decline which mainly depends on the severity of Alzheimer pathology, but in early stage of AD they may influence and promote the development of dementia. Recent studies showed lower density of plaques and tangles in brains with cerebrovascular lesions, and similar severity of dementia was related to fewer AD lesions in brains with than in those without small vascular lesions. Further studies will help to elucidate the risk factors and impact of cerebrovascular lesions on the development and progression of dementia in AD.

Jellinger KA. · Ludwig Boltzmann Institute of Clinical Neurobiology, PKH/B-Building; Baumgartner Hoehe 1, A-1140 Vienna, Austria. · J Cell Mol Med. · Pubmed #12067447 No free full text.

Abstract: Progressive cell loss in specific neuronal populations often associated with typical cytoskeletal protein aggregations is a pathological hallmark of neurodegenerative disorders, but the nature, time course and molecular causes of cell death and their relation to cytoskeletal pathologies are still unresolved. Apoptosis or alternative pathways of cell death have been discussed in Alzheimer's disease and other neurodegenerative disorders. Apoptotic DNA fragmentation in human brain as a sign of neuronal injury is found too frequent as to account for continuous neuron loss in these slowly progressive processes. Morphological studies revealed extremely rare apoptotic neuronal death in Alzheimer's disease but yielded mixed results for Parkinson's disease and other neurodegenerative disorders. Based on recent data in human brain, as well as in animal and cell culture models, a picture is beginning to emerge suggesting that, in addition to apoptosis, other forms of programmed cell death may participate in neurodegeneration. Better understanding of the molecular players will further elucidate the mechanisms of cell death in these disorders and their relations to cytoskeletal abnormalities. Susceptible cell populations in a proapoptotic environment show increased vulnerability towards multiple noxious factors discussed in the pathogenesis of neurodegeneration. In conclusion, although many in vivo and in vitro data are in favor of apoptosis involvement in neurodegenerative processes, there is considerable evidence that very complex events may contribute to neuronal death with possible repair mechanisms, the elucidation of which may prove useful for future prevention and therapy of neurodegenerative disorders.

Jellinger KA. · No affiliation provided · J Neurol Sci. · Pubmed #11790397 No free full text.

This publication has no abstract.

Jellinger KA. · L. Boltzmann-Institut für Klinische Neurobiologie, KH Wien-Lainz, Austria. · Wien Klin Wochenschr. · Pubmed #10526393 No free full text.

Abstract: Alzheimer's disease and other degenerative disorders--dementia with Lewy bodies, frontotemporal dementia, etc.--causing about 90% of dementias in advanced age, are a major health problem of increasing practical, scientific, and socio-economic importance. Despite considerable progress in genetic, clinical and basic neurosciences, the aetiology and molecular mechanisms of these disorders are still unknown and their early diagnosis, due to lack of specific biomarkers, is still unsatisfactory. The epidemiology, risk factors, clinical and morphological diagnostic criteria, probable pathogenic factors, and molecular genetics of the major types of degenerative dementias are reviewed. Their management involves several pharmacologic, non-pharmacologic and psychosocial options. Modification of the disease by reducing known and presumable risk factors, cognitive enhancement with cholinomimetic drugs, and reduction of behavioural abnormalities with psychotropic drugs, together with informed community and private management are currently achievable goals that will serve to delay the progression of disease. In the future, these options will hopefully be replaced by more effective management strategies in order to improve the quality of life of both, patients and caregivers.

Rainer M, Kraxberger E, Haushofer M, Mucke HA, Jellinger KA. · Memory-Clinic and Psychiatric Department, Donauspital, Sozialmedizinisches Zentrum Ost, Wein, Austria. · J Neural Transm. · Pubmed #11459000 No free full text.

Abstract: Reduced nicotinamide adenine dinucleotide (NADH) is advertised as an over-the-counter product or dietary supplement to treat Alzheimer's disease. We performed a 3-month open-label study with oral 10 mg/day NADH with 25 patients with mild to moderate dementia of the Alzheimer, vascular, and fronto-temporal types in addition to their current cholinomimetic drug medication. In 19 patients who completed the study, we found no evidence for any cognitive effect as defined by established psychometric tests. We conclude that NADH is unlikely to achieve cognitive improvements in an extent reported earlier, and present theoretical arguments against an effectiveness of this compound in dementia disorders.

Jellinger KA. · Institute of Clinical Neurobiology, Kenyongasse 18, A-1070, Vienna, Austria. · Alzheimers Dement. · Pubmed #19595916 No free full text.

Abstract: Mixed type dementia (MD) refers to a combination of Alzheimer disease (AD) and vascular encephalopathy (VE) and other dementia disorders, but the distinction between these diseases is difficult. For the diagnosis of MD, the clinical/neuroimaging criteria of probable AD plus vascular cognitive impairment (VCI) as separate entities are used. Both disorders increase exponentially with age, but their interactions are common and controversial. Pathologic diagnosis is based on the combination of autopsy-proven AD with multiple vascular or ischemic brain lesions. The population-based incidence and prevalence of MD is unknown. In retrospective and prospective autopsy studies, its prevalence ranges from 2% to 58% with reasonable means of 6% to 12%, although findings from several recent studies indicated frequent coexistence of AD with multiple cerebrovascular lesions (CVLs) in cognitively impaired elderly subjects. In both AD and VCI, vascular lesions frequently involve subcortical regions (basal ganglia, thalamus, hippocampus, white matter) or are multiple microinfarcts, whereas in MD large/hemispheral infarcts and multiple microinfarcts are more frequent, suggesting different pathogenic mechanisms. There is increasing evidence that critically located small CVLs can induce/promote cognitive impairment in early-stage AD but not once AD pathology becomes more advanced. Discussion of the major pathogenic factors inducing AD, VCI, and MD suggests synergistic relations between these disorders. Currently available clinical and morphologic criteria for AD and VCI are of limited value for the diagnosis of MD, and the ability of current consensus criteria to distinguish between AD, VCI, and MD is limited. Therefore, future development of methods that more accurately characterize the impact of both AD-related and vascular brain injuries are warranted.

Jellinger KA. · Institute of Clinical Neurobiology Kenyongasse 18, A-1070 Vienna, Austria. · Biochim Biophys Acta. · Pubmed #18718530 No free full text.

Abstract: The two most frequent synucleinopathies, Parkinson disease (PD) or brainstem predominant type of Lewy body disease, and dementia with Lewy bodies (DLB), are neurodegenerative multisystem disorders with widespread occurrence of alpha-synuclein containing deposits in the central, peripheral, and autonomic systems. For both Lewy body-related disorders staging/classification systems based on semiquantitative assessment of the distribution and progression pattern of alpha-synuclein pathology are used that are considered to be linked to clinical dysfunctions. In PD a six-stage system is suggested to indicate a predictable sequence of lesions with ascending progression from medullary and olfactory nuclei to the cortex, the first two presymptomatic stages related to incidental Lewy body disease, stages 3 and 4 presenting with motor symptoms and the last two (cortical) stages frequently associated with cognitive impairment. DLB, according to consensus pathologic guidelines, by semiquantitative scoring of alpha-synuclein pathology (Lewy body density and distribution) in specific brain regions, is distinguished into three phenotypes (brainstem, transitory/limbic and diffuse cortical), also considering concomitant Alzheimer-related pathology. Recent retrospective clinico-pathologic studies, although largely confirming the staging system, particularly for younger onset PD with long duration, have shown that between 6.3 and 43% of cases did not follow the proposed caudo-rostral progression pattern of alpha-synuclein pathology. In 7 to 8.3% of clinically manifested PD cases with synuclein inclusions in midbrain and cortex corresponding to LB stages 4-5 the medullary nuclei were spared, whereas mild parkinsonian symptoms were already observed in stages 2 and 3. There is considerable clinical and pathologic overlap between PD (with or without dementia) and DLB, corresponding to Braak LB stages 5 and 6, both frequently associated with variable Alzheimer-type pathology. Dementia often does not correlate with progressed stages of Lewy body pathology, but is related to concomitant Alzheimer lesions or mixed pathologies. There is no relationship between Braak LB stages and clinical severity of PD. Therefore, the predictive validity of this concept is doubtful, since in large unselected autopsy series 30 to 55% of elderly subjects with widespread alpha-synuclein pathology (Braak stages 5-6) revealed no definite neuropsychiatric symptoms or were not classifiable, indicating compensatory mechanisms of the brain. The causes and molecular basis of rather frequent deviations from the proposed caudo-rostral progression of alpha-synuclein pathology in PD, its relation to the onset of classical parkinsonian symptoms, the causes for the lack of definite clinical symptoms despite widespread alpha-synuclein pathology in the nervous system, their relations to Alzheimer-type lesions, and the pathophysiologic impact of both pathologies remain to be further elucidated.

Jellinger KA. · Institute of Clinical Neurobiology, Vienna, Austria. · Neurodegener Dis. · Pubmed #18349518 No free full text.

Abstract: BACKGROUND: The clinical and pathological heterogeneity of progressive supranuclear palsy (PSP) is well established. Recent clinicopathological studies showed much more severe and more widespread tau pathology in Richardson's syndrome (RS), clinically manifest by early onset, falls, supranuclear gaze palsy, dementia and shorter disease duration than in atypical PSP-parkinsonism (PSP-P) often mimicking Parkinson's disease, in which tau pathology is relatively restricted to substantia nigra, subthalamic nucleus and internal globus pallidus. OBJECTIVE: To perform a comparative clinicopathological study of 30 autopsy-proven cases of PSP. METHODS: Retrospective assessment of major clinical signs in 18 patients referred to as RS and 12 PSP-P, and semiquantitative assessment of the severity and distribution pattern of tau pathology in both phenotypes using routine stains and immunohistochemistry. RESULTS: RS (61% males) and PSP-P (33% males) showed significant differences in clinical symptomatology and course (RS mean duration 4.2 years, PSP-P 13.8 years) and significant differences in histopathology: widespread tau pathology and related multisystem degeneration in RS and more restricted lesions in PSP-P, which, however, were not only involving predominantly the subthalamo-nigral-pallidal system. Cortical tau pathology in both groups was usually restricted to limbic areas, and neocortical Alzheimer-type pathology was only seen in very old or demented PSP patients. CONCLUSIONS: The present study confirmed the recently reported existence of two distinct clinical phenotypes in patients with pathologically proven PSP-P and RS, showing significant differences in severity and distribution of tau pathology, the latter more severe and more widely distributed than in PSP-P.