Publications by authors named "Kurt A Jellinger"

188 Publications

Is Multiple System Atrophy a Prion-like Disorder?

Int J Mol Sci 2021 Sep 18;22(18). Epub 2021 Sep 18.

Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria.

Multiple system atrophy (MSA) is a rapidly progressive, fatal neurodegenerative disease of uncertain aetiology that belongs to the family of α-synucleinopathies. It clinically presents with parkinsonism, cerebellar, autonomic, and motor impairment in variable combinations. Pathological hallmarks are fibrillary α-synuclein (αSyn)-rich glial cytoplasmic inclusions (GCIs) mainly involving oligodendroglia and to a lesser extent neurons, inducing a multisystem neurodegeneration, glial activation, and widespread demyelinization. The neuronal αSyn pathology of MSA has molecular properties different from Lewy bodies in Parkinson's disease (PD), both of which could serve as a pool of αSyn (prion) seeds that could initiate and drive the pathogenesis of synucleinopathies. The molecular cascade leading to the "prion-like" transfer of "strains" of aggregated αSyn contributing to the progression of the disease is poorly understood, while some presented evidence that MSA is a prion disease. However, this hypothesis is difficult to reconcile with postmortem analysis of human brains and the fact that MSA-like pathology was induced by intracerebral inoculation of human MSA brain homogenates only in homozygous mutant 53T mice, without production of disease-specific GCIs, or with replication of MSA prions in primary astrocyte cultures from transgenic mice expressing human αSyn. Whereas recent intrastriatal injection of Lewy body-derived or synthetic human αSyn fibrils induced PD-like pathology including neuronal αSyn aggregates in macaques, no such transmission of αSyn pathology in non-human primates by MSA brain lysate has been reported until now. Given the similarities between αSyn and prions, there is a considerable debate whether they should be referred to as "prions", "prion-like", "prionoids", or something else. Here, the findings supporting the proposed nature of αSyn as a prion and its self-propagation through seeding as well as the transmissibility of neurodegenerative disorders are discussed. The proof of disease causation rests on the concordance of scientific evidence, none of which has provided convincing evidence for the classification of MSA as a prion disease or its human transmission until now.
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http://dx.doi.org/10.3390/ijms221810093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472631PMC
September 2021

No Metagenomic Evidence of Causative Viral Pathogens in Postencephalitic Parkinsonism Following Encephalitis Lethargica.

Microorganisms 2021 Aug 12;9(8). Epub 2021 Aug 12.

Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.

Postencephalitic parkinsonism (PEP) is a disease of unknown etiology and pathophysiology following encephalitis lethargica (EL), an acute-onset polioencephalitis of cryptic cause in the 1920s. PEP is a tauopathy with multisystem neuronal loss and gliosis, clinically characterized by bradykinesia, rigidity, rest tremor, and oculogyric crises. Though a viral cause of EL is likely, past polymerase chain reaction-based investigations in the etiology of both PEP and EL were negative. PEP might be caused directly by an unknown viral pathogen or the consequence of a post-infectious immunopathology. The development of metagenomic next-generation sequencing in conjunction with bioinformatic techniques has generated a broad-range tool for the detection of unknown pathogens in the recent past. Retrospective identification and characterization of pathogens responsible for past infectious diseases can be successfully performed with formalin-fixed paraffin-embedded (FFPE) tissue samples. In this study, we analyzed 24 FFPE brain samples from six patients with PEP by unbiased metagenomic next-generation sequencing. Our results show that no evidence for the presence of a specific or putative (novel) viral pathogen was found, suggesting a likely post-infectious immune-mediated etiology of PEP.
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http://dx.doi.org/10.3390/microorganisms9081716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398509PMC
August 2021

Pallidal degenerations and related disorders: an update.

Authors:
Kurt A Jellinger

J Neural Transm (Vienna) 2021 Aug 7. Epub 2021 Aug 7.

Institute of Clinical Neurobiology, Alberichgasse 5/13, 1150, Vienna, Austria.

Neurodegenerative disorders involving preferentially the globus pallidus, its efferet and afferent circuits and/or related neuronal systems are rare. They include a variety of both familial and sporadic progressive movement disorders, clinically manifesting as choreoathetosis, dystonia, Parkinsonism, akinesia or myoclonus, often associated with seizures, mental impairment and motor or cerebellar symptoms. Based on the involved neuronal systems, this heterogenous group has been classified into several subgroups: "pure" pallidal atrophy (PPA) and extended forms, pallidonigral and pallidonigrospinal degeneration (PND, PNSD), pallidopyramidal syndrome (PPS), a highly debatable group, pallidopontonigral (PPND), nigrostriatal-pallidal-pyramidal degeneration (NSPPD) (Kufor-Rakeb syndrome /KRS), pallidoluysian degeneration (PLD), pallidoluysionigral degeneration (PLND), pallidoluysiodentate atrophy (PLDA), the more frequent dentatorubral-pallidoluysian atrophy (DRPLA), and other hereditary multisystem disorders affecting these systems, e.g., neuroferritinopathy (NF). Some of these syndromes are sporadic, others show autosomal recessive or dominant heredity, and for some specific gene mutations have been detected, e.g., ATP13A2/PARK9 (KRS), FTL1 or ATP13A2 (neuroferritinopathy), CAG triple expansions in gene ATN1 (DRPLA) or pA152T variant in MAPT gene (PNLD). One of the latter, and both PPND and DRPLA are particular subcortical 4-R tauopathies, related to progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and frontotemporal lobe degeneration-17 (FTLD-17), while others show additional 3-R and 4-R tauopathies or TDP-43 pathologies. The differential diagnosis includes a large variety of neurodegenerations ranging from Huntington and Joseph-Machado disease, tauopathies (PSP), torsion dystonia, multiple system atrophy, neurodegeneration with brain iron accumulation (NBIA), and other extrapyramidal disorders. Neuroimaging data and biological markers have been published for only few syndromes. In the presence of positive family histories, an early genetic counseling may be effective. The etiology of most phenotypes is unknown, and only for some pathogenic mechanisms, like polyglutamine-induced oxidative stress and autophagy in DRPLA, mitochondrial dysfunction induced by oxidative stress in KRS or ferrostasis/toxicity and protein aggregation in NF, have been discussed. Currently no disease-modifying therapy is available, and symptomatic treatment of hypo-, hyperkinetic, spastic or other symptoms may be helpful.
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http://dx.doi.org/10.1007/s00702-021-02392-2DOI Listing
August 2021

Significance of cerebral amyloid angiopathy and other co-morbidities in Lewy body diseases.

Authors:
Kurt A Jellinger

J Neural Transm (Vienna) 2021 05 29;128(5):687-699. Epub 2021 Apr 29.

Institute of Clinical Neurobiology, Alberichgasse 5/13, 1150, Vienna, Austria.

Lewy body dementia (LBD) and Parkinson's disease-dementia (PDD) are two major neurocognitive disorders with Lewy bodies (LB) of unknown etiology. There is considerable clinical and pathological overlap between these two conditions that are clinically distinguished based on the duration of Parkinsonism prior to development of dementia. Their morphology is characterized by a variable combination of LB and Alzheimer's disease (AD) pathologies. Cerebral amyloid angiopathy (CAA), very common in aged persons and particularly in AD, is increasingly recognized for its association with both pathologies and dementia. To investigate neuropathological differences between LB diseases with and without dementia, 110 PDD and 60 LBD cases were compared with 60 Parkinson's disease (PD) cases without dementia (PDND). The major demographic and neuropathological data were assessed retrospectively. PDD patients were significantly older than PDND ones (83.9 vs 77.8 years; p < 0.05); the age of LB patients was in between both groups (mean 80.2 years), while the duration of disease was LBD < PDD < PDND (mean 6.7 vs 12.5 and 14.3 years). LBD patients had higher neuritic Braak stages (mean 5.1 vs 4.5 and 4.0, respectively), LB scores (mean 5.3 vs 4.2 and 4.0, respectively), and Thal amyloid phases (mean 4.1 vs 3.0 and 2.3, respectively) than the two other groups. CAA was more common in LBD than in the PDD and PDND groups (93 vs 50 and 21.7%, respectively). Its severity was significantly greater in LBD than in PDD and PDND (p < 0.01), involving mainly the occipital lobes. Moreover, striatal Aβ deposition highly differentiated LBD brains from PDD. Braak neurofibrillary tangle (NFT) stages, CAA, and less Thal Aβ phases were positively correlated with LB pathology (p < 0.05), which was significantly higher in LBD than in PDD < PDND. Survival analysis showed worse prognosis in LBD than in PDD (and PDND), which was linked to both increased Braak tau stages and more severe CAA. These and other recent studies imply the association of CAA-and both tau and LB pathologies-with cognitive decline and more rapid disease progression that distinguishes LBD from PDD (and PDND).
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http://dx.doi.org/10.1007/s00702-021-02345-9DOI Listing
May 2021

Morphological differences between dementia with Lewy bodies and Parkinson's disease-dementia.

Authors:
Kurt A Jellinger

Neuropathol Appl Neurobiol 2021 Mar 18. Epub 2021 Mar 18.

Institute of Clinical Neurobiology, Vienna, Austria.

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http://dx.doi.org/10.1111/nan.12708DOI Listing
March 2021

Emergent creativity in frontotemporal dementia.

J Neural Transm (Vienna) 2021 03 12;128(3):279-293. Epub 2021 Mar 12.

Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria.

Numerous papers report on connections between creative work and dementing illness, particularly in frontotemporal dementia (FTD), which may combine with motor neuron disease (FTD-MND). However, the emergence of FTD(-MND) patients' de novo artistic activities is rarely reported and underappreciated. Therefore, the present review summarizes relevant case studies' outcomes, capturing creativity's multifaceted nature. Here, we systematically searched for case reports by paying particular attention to the chronological development of individual patients' clinical symptoms, signs, and life events. We synoptically compared the various art domains to the pattern of brain atrophy, the clinical and pathological FTD subtypes. 22 FTD(-MND) patients were identified with creativity occurring either at the same time (41%) or starting after the disease onset (59%); the median lag between the first manifestation of disease and the beginning of creativity was two years. In another five patients, novel artistic activity was developed by a median of 8 years before the start of dementia symptoms. Artistic activity usually evolved over time with a peak in performance, followed by a decline that was further hampered by physical impairment during disease progression. Early on, the themes and objects depicted were often concrete and realistic, but they could become more abstract or symbolic at later stages. Emergent artistic processes may occur early on in the disease process. They appear to be a communication of inner life and may also reflect an attempt of compensation or "self-healing". The relative preservation of primary neocortical areas such as the visual, auditory, or motor cortex may enable the development of artistic activity in the face of degeneration of association cortical areas and subcortical, deeper central nervous system structures. It is crucial to understand the differential loss of function and an individual's creative abilities to implement caregiver-guided, personalized therapeutic strategies such as art therapy.
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http://dx.doi.org/10.1007/s00702-021-02325-zDOI Listing
March 2021

Different patterns of hippocampal subfield pathology in Lewy body disease and Alzheimer's disease.

Authors:
Kurt A Jellinger

Neuropathol Appl Neurobiol 2021 08 5;47(5):705-706. Epub 2021 Feb 5.

Institute of Clinical Neurobiology, Vienna, Austria.

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http://dx.doi.org/10.1111/nan.12695DOI Listing
August 2021

Pathobiological Subtypes of Alzheimer Disease.

Authors:
Kurt A Jellinger

Dement Geriatr Cogn Disord 2020 11;49(4):321-333. Epub 2021 Jan 11.

Institute of Clinical Neurobiology, Vienna, Austria,

Alzheimer disease (AD), the most common form of dementia, is a heterogenous disorder with various pathobiological subtypes. In addition to the 4 major subtypes based on the distribution of tau pathology and brain atrophy (typical, limbic predominant, hippocampal sparing, and minimal atrophy [MA]), several other clinical variants showing distinct regional patterns of tau burden have been identified: nonamnestic, corticobasal syndromal, primary progressive aphasia, posterior cortical atrophy, behavioral/dysexecutive, and mild dementia variants. Among the subtypes, differences were found in age at onset, sex distribution, cognitive status, disease duration, APOE genotype, and biomarker levels. The patterns of key network destructions parallel the tau and atrophy patterns of the AD subgroups essentially. Interruption of key networks, in particular the default-mode network that is responsible for cognitive decline, is consistent in hetero-genous AD groups. AD pathology is often associated with co-pathologies: cerebrovascular lesions, Lewy pathology, and TDP-43 proteinopathies. These mixed pathologies essentially influence the clinical picture of AD and may accel-erate disease progression. Unraveling the heterogeneity among the AD spectrum entities is important for opening a window to pathogenic mechanisms affecting the brain and enabling precision medicine approaches as a basis for developing preventive and ultimately successful disease-modifying therapies for AD.
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http://dx.doi.org/10.1159/000508625DOI Listing
May 2021

Commentary: Discriminating α-synuclein strains in parkinson's disease and multiple system atrophy.

Front Neurosci 2020 25;14:802. Epub 2020 Aug 25.

Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.3389/fnins.2020.00802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477319PMC
August 2020

Neuropathological assessment of the Alzheimer spectrum.

Authors:
Kurt A Jellinger

J Neural Transm (Vienna) 2020 09 1;127(9):1229-1256. Epub 2020 Aug 1.

Institute of Clinical Neurobiology, Alberichgasse 5/13, 1150, Vienna, Austria.

Alzheimer disease (AD), the most common form of dementia globally, classically defined a clinicopathological entity, is a heterogenous disorder with various pathobiological subtypes, currently referred to as Alzheimer continuum. Its morphological hallmarks are extracellular parenchymal β-amyloid (amyloid plaques) and intraneuronal (tau aggregates forming neurofibrillary tangles) lesions accompanied by synaptic loss and vascular amyloid deposits, that are essential for the pathological diagnosis of AD. In addition to "classical" AD, several subtypes with characteristic regional patterns of tau pathology have been described that show distinct clinical features, differences in age, sex distribution, biomarker levels, and patterns of key network destructions responsible for cognitive decline. AD is a mixed proteinopathy (amyloid and tau), frequently associated with other age-related co-pathologies, such as cerebrovascular lesions, Lewy and TDP-43 pathologies, hippocampal sclerosis, or argyrophilic grain disease. These and other co-pathologies essentially influence the clinical picture of AD and may accelerate disease progression. The purpose of this review is to provide a critical overview of AD pathology, its defining pathological substrates, and the heterogeneity among the Alzheimer spectrum entities that may provide a broader diagnostic coverage of this devastating disorder as a basis for implementing precision medicine approaches and for ultimate development of successful disease-modifying drugs for AD.
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http://dx.doi.org/10.1007/s00702-020-02232-9DOI Listing
September 2020

Neuropathological findings in multiple system atrophy with cognitive impairment.

Authors:
Kurt A Jellinger

J Neural Transm (Vienna) 2020 07 4;127(7):1031-1039. Epub 2020 May 4.

Institute of Clinical Neurobiology, Alberichgasse 5/13, 1150, Vienna, Austria.

Cognitive impairment (CI), previously considered an exclusion criterium for the diagnosis of multiple system atrophy (MSA) according to the second consensus criteria, is not uncommon in MSA. Mild cognitive impairment (MCI) has been reported in up to 47% of MSA patients, while severe dementia is rare. We related clinical CI with neuropathological findings in 48 autopsy-proven cases of MSA. This retrospective study included 33 parkinsonism predominant MSA (MSA-P), and 15 cerebellar ataxia-predominant MSA (MSA-C) cases (mean age at death 60.5 ± 7.8; range 46-82 years). Cognitive state was assessed from hospital charts, however, without comprehensive neuropsychological testing. Neuropathological examination, in addition to grading of the MSA pathologies, included semiquantitative assessment of Lewy and Alzheimer-related co-pathologies. Their incidence was compared with 143 age-matched controls (mean age 60.5 ± 7.6 years). MCI reported in ten cases (20.8%) was associated with moderate cortical tau pathology in only three; moderate CI in seven patients (14.5%) was associated with cortical amyloid plaques and moderate cortical tau pathology in six each, and one with probable primary age-related tauopathy (PART); a female aged 82 years with severe dementia showed fully developed Alzheimer disease. Cortical amyloid plaques, observed in eight cases, three of them without tau pathology, were associated with clinical MCI, as was cortical Lewy pathology in five. Two cases with cortical Lewy pathology and neuritic Braak stages II and III, and three with Braak stage IV, without cortical Lewy bodies, had shown moderate CI. Cortical Lewy pathology observed in four cases was not associated with clinical CI. 77.1% of the MSA cases were free of Alzheimer-type lesions, compared to 42% of controls; while Lewy pathology in the MSA cohort (22.9%) was significantly higher than in the control group (8.4%) both p < 0.001. Mild-to-moderate CI, reported in 35.3% of MSA patients, being significantly older than those without CI, were frequently associated with cortical Alzheimer (Braak stages III and IV) and Lewy pathologies, while only one with severe dementia had fully developed Alzheimer disease. In view of these findings in a limited series of MSA patients, further studies to elucidate the pathological basis of cognitive impairment in MSA are warranted.
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http://dx.doi.org/10.1007/s00702-020-02201-2DOI Listing
July 2020

Striatal dopamine transporter activity may predict β-amyloid pathology in dementia with Lewy bodies.

Authors:
Kurt A Jellinger

Neurology 2020 03 21;94(13):557-558. Epub 2020 Feb 21.

From the Institute of Clinical Neurobiology, Vienna, Austria.

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http://dx.doi.org/10.1212/WNL.0000000000009167DOI Listing
March 2020

Epigallocatechin gallate in multiple system atrophy (PROMESA).

Authors:
Kurt A Jellinger

Ann Transl Med 2019 Dec;7(Suppl 8):S278

Institute of Clinical Neurobiology, Vienna, Austria.

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http://dx.doi.org/10.21037/atm.2019.11.141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976410PMC
December 2019

How can we best care for people with dementia with Lewy bodies pharmacologically?

Authors:
Kurt A Jellinger

Expert Opin Pharmacother 2020 04 14;21(5):513-515. Epub 2020 Jan 14.

Institue of Clinical Neurobiology, Vienna, Austria.

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http://dx.doi.org/10.1080/14656566.2020.1712359DOI Listing
April 2020

Multiple system atrophy and myoclonus: A morphologic marker in the spinal cord?

Neurology 2019 08;93(7):287-288

From Krembil Research Institute (L.V.K.) and Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Division of Neurology, Department of Medicine (L.V.K.), Toronto Western Hospital, University Health Network; Division of Neurology, Department of Medicine (L.V.K.), and Tanz Centre for Research in Neurodegenerative Diseases (L.V.K.), University of Toronto, Canada; and Institute of Clinical Neurobiology (K.A.J.), Vienna, Austria.

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http://dx.doi.org/10.1212/WNL.0000000000007941DOI Listing
August 2019

Traumatic brain injury and Alzheimer's disease neuropathology.

Authors:
Kurt A Jellinger

Alzheimers Dement 2019 09 8;15(9):1236-1237. Epub 2019 Aug 8.

Institute of Clinical Neurobiology, Vienna, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.jalz.2019.06.3917DOI Listing
September 2019

Animal models of synucleinopathies and how they could impact future drug discovery and delivery efforts.

Authors:
Kurt A Jellinger

Expert Opin Drug Discov 2019 10 5;14(10):969-982. Epub 2019 Jul 5.

Institute of Clinical Neurobiology , Vienna , Austria.

: Ample efforts have been carried out to develop efficient disease-modifying drugs of Parkinson's disease and related synucleinopathies. At present, the available animal models appropriate for drug development and delivery for these hitherto incurable disorders are limited. : The author, herein, provides their perspectives on classical toxin-based animal models, which have provided some insight into their clinical picture and complex pathogenesis. They also discuss generic and virus-induced models and more recent αSyn transmitter models that reproduce essential clinical and morphological aspects but do not fully replicate the whole spectrum of the human diseases. Yet, these models have, however, provided new insights into the pathogenesis of these disorders. : The recent development of transgenic viral vector-induced αSyn inoculation models and those using induced pluripotent stem cells (iPSCs) in rodents, non-human primates and (rare) primates, reproducing many but not all aspects of the human synucleinopathies and their complex pathogenesis opened the door for the development of successful drugs. Despite these limits, a remarkable amount of work has already been done. However, further attention should be focused on the development of new models to enable better insight into the pathology of these proteinopathies as the basis for the future development of real disease-modifying or even preventive modalities.
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http://dx.doi.org/10.1080/17460441.2019.1638908DOI Listing
October 2019

Neuropathology and pathogenesis of extrapyramidal movement disorders: a critical update. II. Hyperkinetic disorders.

Authors:
Kurt A Jellinger

J Neural Transm (Vienna) 2019 08 24;126(8):997-1027. Epub 2019 Jun 24.

Institute of Clinical Neurobiology, Alberichgasse 5/13, 1150, Vienna, Austria.

Extrapyramidal movement disorders comprise hypokinetic-rigid and hyperkinetic or mixed forms, most of them originating from dysfunction of the basal ganglia (BG) and their information circuits that have been briefly reviewed in part 1 of the papers on neuropathology and pathogenesis of extrapyramidal movement disorders. The classification of hyperkinetic forms distinguishes the following: (1) chorea and related syndromes; (2) dystonias (dyskinesias); (3) tics and tourette disorders; (4) ballism; (5) myoclonic and startle disorders; and (6) tremor syndromes. Recent genetic and molecular classification distinguishes the following: (1) polyglutamine disorders (Huntington's disease and related disorders); (2) pantothenate kinase associated neurodegeneration; (3) Wilson's disease and related disorders; and (4) other hereditary neurodegenerations without hitherto detected genetic or specific markers. The diversity of phenotypes is related to the deposition of pathologic proteins in distinct cell populations, causing neurodegeneration due to genetic and environmental factors, but there is frequent overlap between various disorders. Their etiopathogenesis is still poorly understood but is suggested to result from an interaction between genetic and environmental factors, multiple etiologies, and noxious factors (protein mishandling, mitochondrial dysfunction, oxidative stress, excitotoxicity, energy failure, chronic neuroinflammation), being more likely than one single factor. Current clinical consensus criteria have increased the diagnostic accuracy of most neurodegenerative movement disorders, but for their definite diagnosis, histopathological confirmation is required. A timely overview of the neuropathology and pathogenesis of the major hyperkinetic movement disorders is presented.
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http://dx.doi.org/10.1007/s00702-019-02030-yDOI Listing
August 2019

Neuropathology and pathogenesis of extrapyramidal movement disorders: a critical update-I. Hypokinetic-rigid movement disorders.

Authors:
Kurt A Jellinger

J Neural Transm (Vienna) 2019 08 18;126(8):933-995. Epub 2019 Jun 18.

Institute of Clinical Neurobiology, Alberichgasse 5/13, 1150, Vienna, Austria.

Extrapyramidal movement disorders include hypokinetic rigid and hyperkinetic or mixed forms, most of them originating from dysfunction of the basal ganglia (BG) and their information circuits. The functional anatomy of the BG, the cortico-BG-thalamocortical, and BG-cerebellar circuit connections are briefly reviewed. Pathophysiologic classification of extrapyramidal movement disorder mechanisms distinguish (1) parkinsonian syndromes, (2) chorea and related syndromes, (3) dystonias, (4) myoclonic syndromes, (5) ballism, (6) tics, and (7) tremor syndromes. Recent genetic and molecular-biologic classifications distinguish (1) synucleinopathies (Parkinson's disease, dementia with Lewy bodies, Parkinson's disease-dementia, and multiple system atrophy); (2) tauopathies (progressive supranuclear palsy, corticobasal degeneration, FTLD-17; Guamian Parkinson-dementia; Pick's disease, and others); (3) polyglutamine disorders (Huntington's disease and related disorders); (4) pantothenate kinase-associated neurodegeneration; (5) Wilson's disease; and (6) other hereditary neurodegenerations without hitherto detected genetic or specific markers. The diversity of phenotypes is related to the deposition of pathologic proteins in distinct cell populations, causing neurodegeneration due to genetic and environmental factors, but there is frequent overlap between various disorders. Their etiopathogenesis is still poorly understood, but is suggested to result from an interaction between genetic and environmental factors. Multiple etiologies and noxious factors (protein mishandling, mitochondrial dysfunction, oxidative stress, excitotoxicity, energy failure, and chronic neuroinflammation) are more likely than a single factor. Current clinical consensus criteria have increased the diagnostic accuracy of most neurodegenerative movement disorders, but for their definite diagnosis, histopathological confirmation is required. We present a timely overview of the neuropathology and pathogenesis of the major extrapyramidal movement disorders in two parts, the first one dedicated to hypokinetic-rigid forms and the second to hyperkinetic disorders.
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http://dx.doi.org/10.1007/s00702-019-02028-6DOI Listing
August 2019

Primary age-related tauopathy (PART) and Alzheimer's disease (AD).

Authors:
Kurt A Jellinger

Alzheimers Dement 2019 05 8;15(5):720. Epub 2019 Mar 8.

Institute of Clinical Neurobiology, Vienna, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.jalz.2019.01.005DOI Listing
May 2019

Parkinsonism in MCI or mild Alzheimer's disease.

Authors:
Kurt A Jellinger

Alzheimers Dement 2019 04 1;15(4):598-599. Epub 2019 Mar 1.

Institute of Clinical Neurobiology, Vienna, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.jalz.2018.12.014DOI Listing
April 2019

Young-onset multiple system atrophy.

Authors:
Kurt A Jellinger

Mov Disord 2018 12;33(12):1974-1975

Institute of Clinical Neurobiology, Vienna, Austria.

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http://dx.doi.org/10.1002/mds.27567DOI Listing
December 2018

Different patterns of hippocampal tau pathology in Alzheimer's disease and PART.

Authors:
Kurt A Jellinger

Acta Neuropathol 2018 11 7;136(5):811-813. Epub 2018 Aug 7.

Institute of Clinical Neurobiology, Alberichgasse 5/13, 1150, Vienna, Austria.

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http://dx.doi.org/10.1007/s00401-018-1894-zDOI Listing
November 2018

Very old onset parkinsonism: A clinical-pathological study.

Authors:
Kurt A Jellinger

Parkinsonism Relat Disord 2018 12 24;57:39-43. Epub 2018 Jul 24.

Institute of Clinical Neurobiology, Alberichgasse 5/13, A-1150, Vienna, Austria. Electronic address:

Background: With increasing age of the world population, the number of parkinsonian patients with disease onset in very old age is expected to increase. Information about the clinical and morphological phenotype of very old age onset parkinsonism is poor, and only three autopsy-confirmed studies of parkinsonian patients of 80 years and older onset are available.

Methods: A retrospective autopsy study of 345 patients clinically diagnosed as Parkinson disease (PD) included 90 cases with disease onset ≥80 years).

Results: Clinically, the majority (60%) presented with a rigid-akinetic phenotype, 13.3% with mixed tremor, akinesia and rigidity, 8.9% tremor-dominant type, 7.8% with tremor + rigidity, 5.6% with tremor-akinesia, and 4.4% with pure akinesia or gait disorder. Additional 8.9% developed hemiparesis, and 80% were demented. In only about 49% of the patients, positive reaction to l-dopa therapy was reported. The progress of disease was accelerated, and survival time (4.34 ± 2.95 SD) was significantly shorter than in younger onset groups. At post mortem examination, only 21 cases (23.3%) revealed Lewy body disease of brainstem type (PD) alone, 44 cases (48.9%) had PD plus Alzheimer disease (AD) (including 6 cases of Lewy body variant of AD). 11% had PD plus cerebrovascular lesions, 6 cases (6.7%) were cerebrovascular disorders and 8 cases (8.9%) were other neurodegenerative diseases (AD, single cases of multiple system atrophy, progressive supranuclear palsy).

Conclusion: The present and other data confirm the clinical and morphological heterogeneity of parkinsonism with shorter survival in the octogenarian population.
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http://dx.doi.org/10.1016/j.parkreldis.2018.07.015DOI Listing
December 2018

Is Braak staging valid for all types of Parkinson's disease?

Authors:
Kurt A Jellinger

J Neural Transm (Vienna) 2019 04 25;126(4):423-431. Epub 2018 Jun 25.

Institute of Clinical Neurobiology, Alberichgasse 5/13, 1150, Vienna, Austria.

Braak et al. proposed that cases with Lewy pathology in the peripheral nervous sytem, spinal cord and brain stem are prodromal Parkinson's disease (PD), suggesting a hypothesized progression of PD pathology. However, the putative potential of peripheral α-synuclein to promote brain pathology has been questioned recently. The Braak staging is a matter of vigorous debate, since < 100% of cases with Lewy pathology fitting the proposed PD staging scheme; however, most studies assessing typical PD cases show that the vast majority (80-100%) fit the Braak staging scheme. Incidental Lewy body disease and PD can show Lewy pathology in substantia nigra or other brain areas without involvement of dorsal motor nucleus of the vagus nerve. The Braak staging system is valid for PD patients with young onset, long duration with motor symptoms, but not for others, e.g., late onset and rapid course PD. The validity of Braak staging and its relationship to various subtypes of PD warrants further studies.
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http://dx.doi.org/10.1007/s00702-018-1898-9DOI Listing
April 2019

Are dementia with Lewy bodies and Parkinson's disease dementia the same disease?

BMC Med 2018 03 6;16(1):34. Epub 2018 Mar 6.

Tel-Aviv University, Sackler Faculty of Medicine, Ramat Aviv, Israel.

Background: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which share many clinical, neurochemical, and morphological features, have been incorporated into DSM-5 as two separate entities of major neurocognitive disorders with Lewy bodies. Despite clinical overlap, their diagnosis is based on an arbitrary distinction concerning the time of onset of motor and cognitive symptoms, namely as early cognitive impairment in DLB and later onset following that of motor symptoms in PDD. Their morphological hallmarks - cortical and subcortical α-synuclein/Lewy body plus β-amyloid and tau pathologies - are similar, but clinical differences at onset suggest some dissimilar profiles. Based on recent publications, including the fourth consensus report of the DLB Consortium, a critical overview is provided herein.

Discussion: The clinical constellations of DLB and PDD include cognitive impairment, parkinsonism, visual hallucinations, and fluctuating attention. Intravitam PET and postmortem studies have revealed a more pronounced cortical atrophy, elevated cortical and limbic Lewy body pathologies, higher Aβ and tau loads in cortex and striatum in DLB compared to PDD, and earlier cognitive defects in DLB. Conversely, multitracer PET studies have shown no differences in cortical and striatal cholinergic and dopaminergic deficits. Clinical management of both DLB and PDD includes cholinesterase inhibitors and other pharmacologic and non-drug strategies, yet with only mild symptomatic effects. Currently, no disease-modifying therapies are available.

Conclusion: DLB and PDD are important dementia syndromes that overlap in many clinical features, genetics, neuropathology, and management. They are currently considered as subtypes of an α-synuclein-associated disease spectrum (Lewy body diseases), from incidental Lewy body disease and non-demented Parkinson's disease to PDD, DLB, and DLB with Alzheimer's disease at the most severe end. Cognitive impairment in these disorders is induced not only by α-synuclein-related neurodegeneration but by multiple regional pathological scores. Both DLB and PDD show heterogeneous pathology and neurochemistry, suggesting that they share important common underlying molecular pathogenesis with Alzheimer's disease and other proteinopathies. While we prefer to view DLB and PDD as extremes on a continuum, there remains a pressing need to more clearly differentiate these syndromes and to understand the synucleinopathy processes leading to either one.
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http://dx.doi.org/10.1186/s12916-018-1016-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840831PMC
March 2018

The Relevance of Iron in the Pathogenesis of Multiple System Atrophy: A Viewpoint.

J Alzheimers Dis 2018 ;61(4):1253-1273

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

Iron is essential for cellular development and maintenance of multiple physiological processes in the central nervous system. The disturbance of its homeostasis leads to abnormal iron deposition in the brain and causes neurotoxicity via generation of free radicals and oxidative stress. Iron toxicity has been established in the pathogenesis of Parkinson's disease; however, its contribution to multiple system atrophy (MSA) remains elusive. MSA is characterized by cytoplasmic inclusions of misfolded α-synuclein (α-SYN) in oligodendrocytes referred to as glial cytoplasmic inclusions (GCIs). Remarkably, the oligodendrocytes possess high amounts of iron, which together with GCI pathology make a contribution toward MSA pathogenesis likely. Consistent with this observation, the GCI density is associated with neurodegeneration in central autonomic networks as well as olivopontocerebellar and striatonigral pathways. Iron converts native α-SYN into a β-sheet conformation and promotes its aggregation either directly or via increasing levels of oxidative stress. Interestingly, α-SYN possesses ferrireductase activity and α-SYN expression underlies iron mediated translational control via RNA stem loop structures. Despite a correlation between progressive putaminal atrophy and iron accumulation as well as clinical decline, it remains unclear whether pathologic iron accumulation in MSA is a secondary event in the cascade of neuronal degeneration rather than a primary cause. This review summarizes the current knowledge of iron in MSA and gives evidence for perturbed iron homeostasis as a potential pathogenic factor in MSA-associated neurodegeneration.
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http://dx.doi.org/10.3233/JAD-170601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798525PMC
January 2019

Dementia with Lewy bodies and Parkinson's disease-dementia: current concepts and controversies.

Authors:
Kurt A Jellinger

J Neural Transm (Vienna) 2018 04 8;125(4):615-650. Epub 2017 Dec 8.

Institute of Clinical Neurobiology, Alberichgasse 5/13, 1150, Vienna, Austria.

Dementia with Lewy bodies (DLB) and Parkinson's disease-dementia (PDD), although sharing many clinical, neurochemical and morphological features, according to DSM-5, are two entities of major neurocognitive disorders with Lewy bodies of unknown etiology. Despite considerable clinical overlap, their diagnosis is based on an arbitrary distinction between the time of onset of motor and cognitive symptoms: dementia often preceding parkinsonism in DLB and onset of cognitive impairment after onset of motor symptoms in PDD. Both are characterized morphologically by widespread cortical and subcortical α-synuclein/Lewy body plus β-amyloid and tau pathologies. Based on recent publications, including the fourth consensus report of the DLB Consortium, a critical overview is given. The clinical features of DLB and PDD include cognitive impairment, parkinsonism, visual hallucinations, and fluctuating attention. Intravitam PET and post-mortem studies revealed more pronounced cortical atrophy, elevated cortical and limbic Lewy pathologies (with APOE ε4), apart from higher prevalence of Alzheimer pathology in DLB than PDD. These changes may account for earlier onset and greater severity of cognitive defects in DLB, while multitracer PET studies showed no differences in cholinergic and dopaminergic deficits. DLB and PDD sharing genetic, neurochemical, and morphologic factors are likely to represent two subtypes of an α-synuclein-associated disease spectrum (Lewy body diseases), beginning with incidental Lewy body disease-PD-nondemented-PDD-DLB (no parkinsonism)-DLB with Alzheimer's disease (DLB-AD) at the most severe end, although DLB does not begin with PD/PDD and does not always progress to DLB-AD, while others consider them as the same disease. Both DLB and PDD show heterogeneous pathology and neurochemistry, suggesting that they share important common underlying molecular pathogenesis with AD and other proteinopathies. Cognitive impairment is not only induced by α-synuclein-caused neurodegeneration but by multiple regional pathological scores. Recent animal models and human post-mortem studies have provided important insights into the pathophysiology of DLB/PDD showing some differences, e.g., different spreading patterns of α-synuclein pathology, but the basic pathogenic mechanisms leading to the heterogeneity between both disorders deserve further elucidation. In view of the controversies about the nosology and pathogenesis of both syndromes, there remains a pressing need to differentiate them more clearly and to understand the processes leading these synucleinopathies to cause one disorder or the other. Clinical management of both disorders includes cholinesterase inhibitors, other pharmacologic and nonpharmacologic strategies, but these have only a mild symptomatic effect. Currently, no disease-modifying therapies are available.
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http://dx.doi.org/10.1007/s00702-017-1821-9DOI Listing
April 2018

Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry.

World J Biol Psychiatry 2018 06 27;19(4):244-328. Epub 2017 Oct 27.

ak Nuffield Department of Clinical Neurosciences , University of Oxford , Oxford , UK.

In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimer's disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-β positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.
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http://dx.doi.org/10.1080/15622975.2017.1375556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916324PMC
June 2018

Brain monoamine oxidases in human parkinsonian disorders.

Authors:
Kurt A Jellinger

Brain 2017 09;140(9):2262-2264

Institute of Clinical Neurobiology, Alberichgasse 5/13, A-1150 Vienna, Austria.

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http://dx.doi.org/10.1093/brain/awx190DOI Listing
September 2017
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