Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series

Kovács, Gábor G.; Milenković, Ivan; Wöhrer, Adelheid; Höftberger, Romana; Gelpí, Ellen; Haberler, Christine; Hönigschnabl, Selma; Reiner-Concin, Angelika; Heinzl, Harald; Jungwirth, Susanne; Krampla, Wolfgang; Fischer, Peter; Budka, Herbert

doi:10.1007/s00401-013-1157-y

Cited by 279 publications

(305 citation statements)

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“…In addition to evaluating cases with only AD-type tau pathology, we also pooled cases with different concomitant tau pathologies together, since these cases are more representative of ageing in the human brain [35,36]. We detected a weaker correlation between LGN and occipital pathology.…”

Section: Discussionmentioning

confidence: 99%

Patterns of Tau and α-Synuclein Pathology in the Visual System

Rahimi

Milenković

Kovács

2015

JPD

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Abstract.Background: Spreading of misfolded proteins has been suggested for neurodegenerative diseases. The hierarchical distribution of protein deposits in Alzheimer's (AD) and Parkinson's disease (PD) supports this concept. Objectives: To evaluate ␣-synuclein and tau-deposition in the optic pathway as an excellent anatomical model, which follows a strict trajectory including a cortico-geniculate feedback connection. Methods: We immunostained the optic nerve, lateral geniculate nucleus (LGN), and occipital cortex for AT8 (phosphorylated tau), ␣-synuclein, and disease-associated prion protein (PrP) in 47 cases with tau pathology (AD type, argyrophilic grain disease, or progressive supranuclear palsy), 16 PD, and 5 Creutzfeldt-Jakob disease (CJD) cases, respectively. Results: We detected immunoreactivity for all proteins along the optic pathway. The optic nerve showed immunopositivity only in cases with tau (6/8, 75%) or ␣-synuclein (5/7, 71%) pathology. The LGN was involved also frequently (tau: 22/47, 46.8%; ␣-synuclein: 15/16, 93.7%; PrP 5/5, 100%). The occipital cortex was variably affected by tau or ␣-synuclein pathology, but always showed PrP immunoreactivity in the CJD cases. Tau pathology in the LGN correlated with tau immunoreactivity in the occipital cortex and Braak stages of neurofibrillary degeneration. In tauopathies, which do not involve the occipital cortex, like argyrophilic grain disease or progressive supranuclear palsy, tau pathology was more frequently astrocytic in the LGN. Conclusions: Our results have implications 1) for the understanding of disease spreading along neural pathways and 2) for the diagnostic evaluation of the visual system in neurodegenerative proteinopathies as a potential biomarker to evaluate disease progression or subgrouping of cases.

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Section: Discussionmentioning

confidence: 99%

Patterns of Tau and α-Synuclein Pathology in the Visual System

Rahimi

Milenković

Kovács

2015

JPD

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“…showed Aβ deposits (68.7%), CVLs (48.9%), non-Alzheimer tauopathies (23.2%), TDP proteinopathy (13.3%), and others (inflammation, tumors, etc, 15.1%). Most of these lesions did not increase the probability of the co-occurrence of others, while the number of observed pathologies correlated significantly with AD-neuropathologic changes [289]. A recent cross-sectional study in a community-based sample of 72 cognitively normal older individuals (mean age 74.9 ± 5.7 years) confirmed that a substantial number harbor neurodegeneration without Aβ burden, but association of neurodegenerative lesions with CVD can emerge through non-Aβ pathways within regions most affected by AD [222].…”

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confidence: 80%

“…), and was over 40% in a large autopsy series of patients over age 80 [270] (Table 4). The burden of vascular and AD type pathologies are considered to be independent of each other, and are consistent with an additive or synergistic effect of both types of lesions on cognitive impairment [147,175,185,272,[286][287][288][289][290][291]. The thresholds for vascular and degenerative lesions in distinguishing "pure" VaD or AD from mixed cases have been discussed [274,292,293].…”

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confidence: 99%

Neuropathology of Dementia Disorders

Jellinger¹

2014

J Alzheimers Dis Parkinsonism

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IntroductionDementia, encompassing deficits in several cognitive domains that are severe enough to interfere with daily functioning [1], in the new DSM V classification is classified within the broad category of major neurocognitive disorders, proposing specific criteria for the various etiologies [2]. Previously defined as the manifestation of deteriorating brain functions over time due to cell deaths in the brain caused by neurodegeneration or any other disease [3], according to recent research dementia is not primarily caused by neuronal cell death/loss, but by dysfunction and loss of synapses [4] in AD [5] and in α-synucleinopathies [6]. Other causes include cholinergic neuronal and axonal abnormalities [7,8], as well as pre-and postsynaptic cortical cholinergic deficits also occurring in early AD [9]. These changes due to disconnection of major nervous circuitries causing default networks [10][11][12][13] have been demonstrated in vivo in early AD [14], suggesting that disease progress is transmitted by neuronal pathways [15]. A prionlike spread of misfolded protein aggregates in the pathogenesis and progression of neurodegeneration is a hot spot of discussion [16][17][18][19][20][21].Both the prevalence and incidence of dementia increase exponentially with age. In 2010, 35.6 million people worldwide lived with dementia, with around 8 million new cases every year. Numbers are expected to double or triple every 5-10 years, to 135 millions in 2050, 16 millions in Europe. In 2010, 58% of all demented people lived in low-cost countries, with their proportion anticipated to rise to 71% in 2050 [22]. According to recent data from China the incidence of dementia was 9.87/1000 person years and the median standardised mortality ratio was 1.94:1 [23]. With the disproportional growth of the elderly population, dementia has become a major public health and socio-economic problem that threatens to become the scourge of our century. The total costs for dementia were US$ 604 billion in 2010 worldwide, up to 70% for social care alone [24], total payments for AD for 2013 were expected to be $ 203 billion in USA alone, not included contributions of unpaid caregivers [25]. Neuropathology of Dementia DisordersKurt A Jellinger* Institute of Clinical Neurobiology, Kenyongasse 18, A 1070, Vienna, Austria AbstractDementia, being not a specific disease but a syndrome characterized by deficits in several cognitive domains, is a major public health and socio-economic problem of our century. It is caused by dysfunction/loss of synapses and neurons inducing default neuronal networks. Despite updated concensus criteria for the clinical diagnosis of the major neurodegenerative disorders and new biomarkers, the diagnostic accuracy ranges from 65 to 96% (for Alzheimer's disease /AD), with a sensitivity versus other dementias of around 85.4% and a specificity of up to 77.7%. Pathologic assessment, using genetic and molecular biological methods, based on homogenous definitions, harmonized interlaboratory and assessment standards, can achiev...

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“…(34) It has even been debated whether subjects with PART represent an early stage of AD or merely reflect a neurodegenerative process at an early stage. (35) Also, "acute or incidental" aS pathology has been reported to be seen in 5% to 31% of the cognitively unimpaired aged subjects (36,37), and Ab has been reported in the cortex of 39% to 82% of cognitively unimpaired aged subjects (38,39). TDP43 pathology has been reported in 3% to 40% of cognitively unimpaired aged subjects.…”

Section: Aging and Nddmentioning

confidence: 99%

New Insight in The Molecular Mechanisms of Neurodegenerative Disease

2018

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B ACKGROUND:Redox and proteotoxic stress contributes to age-dependent accumulation of dysfunctional mitochondria and protein aggregates, and is associated with neurodegeneration. The free radical theory of aging inspired many studies using reactive species scavengers such as alpha-tocopherol, ascorbate and coenzyme-Q to suppress the initiation of oxidative stress. However, clinical trials have had limited success in the treatment of neurodegenerative diseases (NDDs). CONTENT:The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of NDDs. In Alzheimer's disease, the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism, corruptive protein templating. The accumulation of redox modified proteins or organelles cannot be reversed by oxidant intercepting antioxidants and must then be removed by alternative mechanisms. Autophagy serves this essential function in removing damaged or dysfunctional proteins and organelles thus preserving neuronal function and survival.SUMMARY: Senescent cells and their senescenceassociated secretory phenotypes (SASPs) may constitute a novel, understudied, and potentially important contributor to neuro-inflammation and subsequent neurodegeneration. Characterization of cellular senescence in the brain could uncover novel therapeutic targets for the prevention and treatment of chronic age-related NDDs. KEYwORDS

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Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series

Cited by 279 publications

References 93 publications

Patterns of Tau and α-Synuclein Pathology in the Visual System

Patterns of Tau and α-Synuclein Pathology in the Visual System

Neuropathology of Dementia Disorders

New Insight in The Molecular Mechanisms of Neurodegenerative Disease

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