| 1. |
- Crary, John F., et al.
(author)
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Primary age-related tauopathy (PART) : a common pathology associated with human aging
- 2014
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In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 128:6, s. 755-766
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Journal article (peer-reviewed)abstract
- We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (A beta) plaques. For these "NFT+/A beta-aEuroe brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of A beta accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
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| 2. |
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| 3. |
- Kovacs, Gabor G., et al.
(author)
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Aging-related tau astrogliopathy (ARTAG) : harmonized evaluation strategy
- 2016
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In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 131:1, s. 87-102
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Journal article (peer-reviewed)abstract
- Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.
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| 4. |
- Lewczuk, Piotr, et al.
(author)
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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.
- 2018
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In: The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry. - : Informa UK Limited. - 1814-1412. ; 19:4, s. 244-328
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Journal article (peer-reviewed)abstract
- 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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| 5. |
- McAleese, Kirsty E., et al.
(author)
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Post-mortem assessment in vascular dementia : advances and aspirations
- 2016
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In: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 14
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Journal article (peer-reviewed)abstract
- Background: Cerebrovascular lesions are a frequent finding in the elderly population. However, the impact of these lesions on cognitive performance, the prevalence of vascular dementia, and the pathophysiology behind characteristic in vivo imaging findings are subject to controversy. Moreover, there are no standardised criteria for the neuropathological assessment of cerebrovascular disease or its related lesions in human post-mortem brains, and conventional histological techniques may indeed be insufficient to fully reflect the consequences of cerebrovascular disease. Discussion: Here, we review and discuss both the neuropathological and in vivo imaging characteristics of cerebrovascular disease, prevalence rates of vascular dementia, and clinico-pathological correlations. We also discuss the frequent comorbidity of cerebrovascular pathology and Alzheimer's disease pathology, as well as the difficult and controversial issue of clinically differentiating between Alzheimer's disease, vascular dementia and mixed Alzheimer's disease/vascular dementia. Finally, we consider additional novel approaches to complement and enhance current post-mortem assessment of cerebral human tissue. Conclusion: Elucidation of the pathophysiology of cerebrovascular disease, clarification of characteristic findings of in vivo imaging and knowledge about the impact of combined pathologies are needed to improve the diagnostic accuracy of clinical diagnoses.
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| 6. |
- Nelson, Peter T., et al.
(author)
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Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status : A Review of the Literature
- 2012
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In: Journal of Neuropathology and Experimental Neurology. - 0022-3069 .- 1554-6578. ; 71:5, s. 362-381
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Research review (peer-reviewed)abstract
- Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. beta-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of AA plaques and neurofibrillary tangles. Although AA plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.
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| 7. |
- Rauramaa, Tuomas, et al.
(author)
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Cardiovascular diseases and hippocampal infarcts
- 2011
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In: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 21:3, s. 281-287
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Journal article (peer-reviewed)abstract
- The prevalence of hippocampal lesions such as hippocampal infarcts have not been studied in detail even though hippocampal alterations are known to be associated with various clinical conditions such as age-related degenerative disorders and epilepsy. Methods: Here we defined the hippocampal infarcts and assessed the prevalence of this lesion in large unselected population of 1,245 subjects age ranging from 1 to 99 years (mean age 79 +/- 1 S.E.M). Furthermore, we assessed the association of these lesions with various cardio- and cerebro-vascular disorders and other neurodegenerative lesions. The prevalence of hippocampal infarct in the study population of 1,245 subjects was 12%, increasing to 13% when only those with a clinically diagnosed cognitive impairment (n = 311) were analyzed. Large hemispheric brain infarcts were seen in 31% of the study subjects and these lesions were strongly associated with cardiovascular risk factors such as hypertension (43%), coronary disease (32%), myocardial infarct (22%), atrial fibrillation (20%), and heart failure (20%). In contrast, hippocampal infarcts displayed a significant association only with large hemispheric brain infarct, heart failure, and cardiovascular index as assessed postmortem. It is noteworthy that only widespread hippocampal infarcts were associated with clinical symptoms of cognitive impairment or epilepsy. The surprisingly low prevalence of 12% of hippocampal infarcts in aged population found here and the failure to detect an association between this lesion and various cerebro- cardio-vascular lesions is intriguing. Whether susceptibility to ischemia in line with susceptibility to neuronal degeneration in this region is influenced by still undetermined risk- factors need further investigation. Furthermore it should be noted that the size of the hippocampal tissue damage, i.e., small vs. large cystic infarcts is of significance regarding clinical alterations.
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| 8. |
- Rauramaa, Tuomas, et al.
(author)
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Consensus Recommendations on Pathologic Changes in the Hippocampus : A Postmortem Multicenter Inter-Rater Study
- 2013
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In: Journal of Neuropathology and Experimental Neurology. - 0022-3069 .- 1554-6578. ; 72:6, s. 452-461
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Journal article (peer-reviewed)abstract
- There is no consensus on the pathologic conditions or severity implied by the term "hippocampal sclerosis" (HS). In this study, a panel of experienced neuropathologists evaluated inter-rater agreement for pathologic diagnoses in the hippocampus and proposes consensus recommendations on the use of the term "HS." In a group of 251 cases of HS selected from a large autopsy cohort (1,388; 18%), a coordinating group identified 5 patterns of degenerative or vascular pathology. Four independent neuropathologists assessed a single set of hematoxylin and eosin-stained sections following descriptive definitions to classify the appearances and assign the diagnosis of HS, if appropriate. Diagnostic agreement (range, 36%-70%) was highest for vascular lesions. Subsequent joint review of all cases highlighted the need to identify neurodegenerative lesions using immunohistochemistry. Initial agreement in assigning the diagnosis of HS varied from 0% to 86%. After a joint review, the group recommended that the term "HS" should be applied to all cases with complete/near-complete neuronal loss and gliosis in the subfields of the cornu Ammonis but not to hippocampal microinfarction. Therefore, the etiology of HS must be defined in association with a neurodegenerative process or as "lacking neurodegenerative markers," a pathologic condition presumed to arise from hypoxic/ischemic mechanisms.
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| 9. |
- Rauramaa, Tuomas, et al.
(author)
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TAR-DNA binding protein-43 and alterations in the hippocampus
- 2011
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In: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 118:5, s. 683-689
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Journal article (peer-reviewed)abstract
- Immunocytochemistry for transactive response binding protein-43 (TDP43) was assessed in the granular cell layer of the dentate gyrus in 250 cases displaying hippocampal pathology identified by haematoxylin-eosin staining. 18%, nearly one in five displayed TDP43 immunoreactive pathology in the granular cell layer of hippocampus. This percentage increased to 43% when only subjects with hippocampal pathology other than vascular in origin were included. When only subjects with severe Alzheimer's disease-related pathology were included, 42% displayed TDP43-immunoreactive pathology, increasing to 60% when concomitant Alzheimer's disease and alpha-synuclein pathology were present. Within this setting, TDP43-immunoreactive pathology was observed to be present in 6% of subjects with hippocampal pathology but without any cognitive impairment. Our findings justify assessment of TDP43 pathology in every case where a pathological alteration is observed in the hippocampus using a routine stain.
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| 10. |
- Willis, Michael, et al.
(author)
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Chromogranin B and Secretogranin II in transgenic mice overexpressing human APP751 with the London (V717I) and Swedish (K670M/N671L) mutations and in Alzheimer patients
- 2008
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 13:2, s. 123-135
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Journal article (peer-reviewed)abstract
- Chromogranin B and secretogranin II are major soluble constituents of large dense core vesicles of presynaptic structures and have been found in neuritic plaques of Alzheimer patients. We examined the distribution and expression of these peptides in both transgenic mice over expressing human amyloid-beta protein precursor APP751 with the London (V717I) and Swedish (K670M/N671L) mutations and in human post-mortem brain. In transgenic mice, the number of amyloid-beta plaques and chromogranin immunopositive plaques increased from 6 to 12 months. About 60% of amyloid-beta plaques were associated with chromogranin B and about 40% with secretogranin II. Chromogranin immunoreactivity appeared mainly as swollen dystrophic neurites. Neither synaptophysin- nor glial fibrillary acidic protein- immunoreactivity was expressed in chromogranin immunoreactive structures at any timepoint. Density of chromogranin peptides in hippocampal structures did not change in transgenic animals at any timepoint, even though animals had a poorer performance in the Morris water maze task. In conclusion, our findings in transgenic animals partly resembled findings in Alzheimer patients. Chromogranin peptides were associated with amyloid-beta plaques, but were not reduced in specific brain areas as previously reported by our group. Therefore specific changes of chromogranin peptides observed in Alzheimer patients can be related to amyloid-beta pathology only.
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