| 1. |
- Aho, Leena, et al.
(författare)
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Systematic appraisal using immunohistochemistry of brain pathology in aged and demented subjects.
- 2008
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 25:5, s. 423-32
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIMS: Abnormal processing of hyperphosphorylated tau (HPtau), amyloid-beta (Abeta) and alpha-synuclein (alphaS) proteins is considered as causative with regard to the clinical symptoms in age-related neurodegenerative diseases.METHODS: In this retrospective, postmortem study applying immunohistochemical methodology, we assessed Alzheimer's-disease (AD)-related HPtau and Abeta pathology in 178 subjects with alphaS pathology.RESULTS: These pathologies were frequently seen concomitantly, i.e. HPtau in 83% and Abeta in 62% of the alphaS-positive cases. Furthermore, the striatum was frequently involved, particularly in subjects with cognitive impairment (65%). The predictive value of widespread HPtau pathology, i.e. stages V-VI, with respect to cognitive impairment was high, since all 18 subjects presenting with this stage were demented. In contrast, the predictive value of widespread alphaS pathology, i.e. stages 5-6 according to Braak's Parkinson disease staging, was debatable. Fifty-three percent of the subjects with widespread alphaS pathology and no or mild AD-related HPtau pathology were cognitively unimpaired. It is noteworthy that striatal Abeta pathology was more often seen in demented subjects independently of HPtau and/or alphaS status.CONCLUSION: The causative pathology in subjects with clinically diagnosed dementia with Lewy bodies needs to be clarified in future studies.
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| 2. |
- Alafuzoff, Irina, et al.
(författare)
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Assessment of alpha-synuclein pathology : a study of the BrainNet Europe Consortium.
- 2008
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Ingår i: Journal of Neuropathology and Experimental Neurology. - : Oxford University Press (OUP). - 0022-3069 .- 1554-6578. ; 67:2, s. 125-43
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Tidskriftsartikel (refereegranskat)abstract
- To determine the reliability of assessment of alpha-synuclein-immunoreactive (alphaS-IR) structures by neuropathologists, 28 evaluators from 17 centers of BrainNet Europe examined current methods and reproducibility of alphaS-IR evaluation using a tissue microarray (TMA) technique. Tissue microarray blocks were constructed of samples from the participating centers that contained alphaS-IR structures. Slides from these blocks were stained in each center and assessed for neuronal perikaryal inclusions, neurites, and glial cytoplasmic inclusions. The study was performed in 2 phases. First, the TMA slides were stained with the antibody of the center's choice. In this phase, 59% of the sections were of good or acceptable quality, and 4 of 9 antibodies used performed consistently. Differences in interpretation and categorization of alphaS-IR structures, however, led to differing results between the laboratories. Prior to the second phase, the neuropathologists participated in a training session on the evaluation of alphaS-IR structures. Based on the results of the first phase, selected antibodies using designated antigen retrieval methods were then applied to TMA slides in the second phase. When the designated methods of both staining and evaluation were applied, all 26 subsequently stained TMA sections evaluated were of good/acceptable quality, and a high level of concordance in the assessment of the presence or absence of specific alphaS-IR structures was achieved. A semiquantitative assessment of alphaS-IR neuronal perikaryal inclusions yielded agreements ranging from 49% to 82%, with best concordance in cortical core samples. These results suggest that rigorous methodology and dichotomized assessment (i.e. determining the presence or absence of alphaS-IR) should be applied, and that semiquantitative assessment can be recommended only for the cortical samples. Moreover, the study demonstrates that there are limitations in the scoring of alphaS-IR structures.
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| 3. |
- Alafuzoff, Irina, et al.
(författare)
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Staged pathology in Parkinson's disease
- 2014
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Ingår i: Parkinsonism & Related Disorders. - 1353-8020 .- 1873-5126. ; 20:Suppl. 1, s. S57-S61
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Tidskriftsartikel (refereegranskat)abstract
- There has been a tremendous development since a regional progression of pathology in subjects with Lewy bodies (LB) was initially proposed 30 years ago. The entity of dementia with Lewy bodies has been acknowledged, the main protein constituent of LBs--aggregated α-synuclein (αS)--has been identified and a stepwise progression of the pathology has been reported. Implementation of the staging strategies published provides a common ground for handling a case with a suspected α-synucleinopathy. It is always important to state the staging strategy implemented while assessing a case, as the strategy applied might influence both the reported stage of LB pathology and, ultimately, the final diagnosis of the patient.
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| 4. |
- Alafuzoff, Irina, et al.
(författare)
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Staging/typing of Lewy body related alpha-synuclein pathology : a study of the BrainNet Europe Consortium
- 2009
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 117:6, s. 635-652
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Tidskriftsartikel (refereegranskat)abstract
- When 22 members of the BrainNet Europe (BNE) consortium assessed 31 cases with alpha-synuclein (alphaS) immunoreactive (IR) pathology applying the consensus protocol described by McKeith and colleagues in 2005, the inter-observer agreement was 80%, being lowest in the limbic category (73%). When applying the staging protocol described by Braak and colleagues in 2003, agreement was only 65%, and in some cases as low as 36%. When modifications of these strategies, i.e., McKeith's protocol by Leverenz and colleagues from 2009, Braak's staging by Müller and colleagues from 2005 were applied then the agreement increased to 78 and 82%, respectively. In both of these modifications, a reduced number of anatomical regions/blocks are assessed and still in a substantial number of cases, the inter-observer agreement differed significantly. Over 80% agreement in both typing and staging of alphaS pathology could be achieved when applying a new protocol, jointly designed by the BNE consortium. The BNE-protocol assessing alphaS-IR lesions in nine blocks offered advantages over the previous modified protocols because the agreement between the 22 observers was over 80% in most cases. Furthermore, in the BNE-protocol, the alphaS pathology is assessed as being present or absent and thus the quality of staining and the assessment of the severity of alphaS-IR pathology do not alter the inter-observer agreement, contrary to other assessment strategies. To reach these high agreement rates an entity of amygdala-predominant category was incorporated. In conclusion, here we report a protocol for assessing alphaS pathology that can achieve a high inter-observer agreement for both the assignment to brainstem, limbic, neocortical and amygdala-predominant categories of synucleinopathy and the Braak stages.
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| 5. |
- Bras, Jose, et al.
(författare)
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Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies.
- 2014
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 23:23, s. 6139-6146
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Tidskriftsartikel (refereegranskat)abstract
- Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
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| 6. |
- Guerreiro, Rita, et al.
(författare)
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Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases.
- 2016
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 38, s. 7-214
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Tidskriftsartikel (refereegranskat)abstract
- The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD.
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| 7. |
- Kun-Rodrigues, Celia, et al.
(författare)
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A comprehensive screening of copy number variability in dementia with Lewy bodies.
- 2019
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 75
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Tidskriftsartikel (refereegranskat)abstract
- The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.
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| 8. |
- Kun-Rodrigues, Celia, et al.
(författare)
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Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies
- 2017
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 49
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Tidskriftsartikel (refereegranskat)abstract
- . C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis and frontotemporal dementia. To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken to assess the role of . C9orf72 repeat expansions in the disease. Here, we investigated the prevalence of . C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that . C9orf72 repeat expansions are not causally associated with DLB.
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| 9. |
- Parkkinen, Laura, et al.
(författare)
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Applicability of current staging/categorization of alpha-synuclein pathology and their clinical relevance.
- 2008
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 115:4, s. 399-407
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Tidskriftsartikel (refereegranskat)abstract
- In Parkinson's disease (PD) and dementia with Lewy bodies (DLB) alpha-synuclein (alphaS) pathology is seen that displays a predictable topographic distribution. There are two staging/categorization systems, i.e. Braak's and McKeith's, currently in use for the assessment of alphaS pathology. The aim of these diagnostic strategies in pathology is, in addition to assess the stage/severity of pathology, to assess the probabilities of the related clinical symptomatology i.e. dementia and extrapyramidal symptoms (EPS). Herein, we assessed the applicability of these two staging/categorization systems and the frequency of dementia and EPS in a cohort of 226 alphaS-positive-subjects. These subject were selected from a large autopsy sample (n = 1,720), irrespective of the clinical presentation, based on the detection of alphaS-immunoreactivity (IR) in one of the most vulnerable nuclei; in the dorsal motor nucleus of vagus, substantia nigra and basal forebrain. The frequency of alphaS-IR lesions in this large cohort was 14% (248 out of 1,720). If applicable, each of the 226 subjects with all required material available was assigned a neuropathological stage/category of PD/DLB and finally the neuropathological data was analyzed in relation to dementia and EPS. 83% of subjects showed a distribution pattern of alphaS-IR that was compatible with the current staging/categorization systems. Around 55% of subjects with widespread alphaS pathology (Braak's PD stages 5-6) lacked clinical signs of dementia or EPS. Similarly, in respect to those subjects that fulfilled the McKeith criteria for diffuse neocortical category and displaying only mild concomitant Alzheimer's disease-related pathology, only 48% were demented and 54% displayed EPS. It is noteworthy that some subjects (17%) deviated from the suggested caudo-rostral propagation suggesting alternative routes of progression, perhaps due to concomitant diseases and genetic predisposition. In conclusion, our results do indeed confirm that current staging/categorization systems can readily be applied to most of the subjects with alphaS pathology. However, finding that around half of the subjects with abundant alphaS pathology remain neurologically intact is intriguing and raises the question whether we do assess the actual disease process.
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| 10. |
- Rauramaa, Tuomas, et al.
(författare)
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Cardiovascular diseases and hippocampal infarcts
- 2011
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Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 21:3, s. 281-287
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Tidskriftsartikel (refereegranskat)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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