| 1. |
- Berntsson, Shala Ghaderi, et al.
(författare)
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Perfusion and diffusion MRI combined with (11)C-methionine PET in the preoperative evaluation of suspected adult low-grade gliomas
- 2013
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Ingår i: Journal of Neuro-Oncology. - : Springer Science and Business Media LLC. - 0167-594X .- 1573-7373. ; 114:2, s. 241-249
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Tidskriftsartikel (refereegranskat)abstract
- Perfusion and diffusion magnetic resonance imaging (pMRI, dMRI) are valuable diagnostic tools for assessing brain tumors in the clinical setting. The aim of this study was to determine the correlation of pMRI and dMRI with (11)C-methionine positron emission tomography (MET PET) in suspected low-grade gliomas (LGG) prior to surgery. Twenty-four adults with suspected LGG were enrolled in an observational study and examined by MET PET, pMRI and dMRI. Histological tumor diagnosis was confirmed in 23/24 patients (18 gliomas grade II, 5 gliomas grade III). The maximum relative cerebral blood volume (rCBVmax) and the minimum mean diffusivity (MDmin) were measured in tumor areas with highest MET uptake (hotspot) on PET by using automated co-registration of MRI and PET scans. A clearly defined hotspot on PET was present in all 23 tumors. Regions with rCBVmax corresponded with hotspot regions in all tumors, regions with MDmin corresponded with hotspot regions in 20/23 tumors. The correlation between rCBVmax (r = 0.19, P = 0.38) and MDmin (r = -0.41, P = 0.053) with MET uptake in the hotspot was not statistically significant. Taken into account the difficulties of measuring perfusion abnormalities in non-enhancing gliomas, this study demonstrates that co-registered MET PET and pMRI facilitates the identification of regions with rCBVmax. Furthermore, the lack of a clear positive correlation between tumor metabolism in terms of MET uptake and tumor vascularity measured as rCBVmax suggests that combined pMRI/PET provides complementary baseline imaging data in these tumors.
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| 2. |
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| 3. |
- Abu Hamdeh, Sami, et al.
(författare)
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Brain tissue Aβ42 levels are linked to shunt response in idiopathic normal pressure hydrocephalus
- 2019
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Ingår i: Journal of Neurosurgery. - : Journal of Neurosurgery Publishing Group (JNSPG). - 0022-3085 .- 1933-0693. ; 130:1, s. 121-129
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Tidskriftsartikel (refereegranskat)abstract
- Objective The authors conducted a study to test if the cortical brain tissue levels of soluble amyloid beta (Aβ) reflect the propensity of cortical Aβ aggregate formation and may be an additional factor predicting surgical outcome following idiopathic normal pressure hydrocephalus (iNPH) treatment.Methods Highly selective ELISAs (enzyme-linked immunosorbent assays) were used to quantify soluble Aβ40, Aβ42, and neurotoxic Aβ oligomers/protofibrils, associated with Aβ aggregation, in cortical biopsy samples obtained in patients with iNPH (n = 20), sampled during ventriculoperitoneal (VP) shunt surgery. Patients underwent pre- and postoperative (3-month) clinical assessment with a modified iNPH scale. The preoperative CSF biomarkers and the levels of soluble and insoluble Aβ species in cortical biopsy samples were analyzed for their association with a favorable outcome following the VP shunt procedure, defined as a ≥ 5-point increase in the iNPH scale.Rrsults The brain tissue levels of Aβ42 were negatively correlated with CSF Aβ42 (Spearman's r = -0.53, p < 0.05). The Aβ40, Aβ42, and Aβ oligomer/protofibril levels in cortical biopsy samples were higher in patients with insoluble cortical Aβ aggregates (p < 0.05). The preoperative CSF Aβ42 levels were similar in patients responding (n = 11) and not responding (n = 9) to VP shunt treatment at 3 months postsurgery. In contrast, the presence of cortical Aβ aggregates and high brain tissue Aβ42 levels were associated with a poor outcome following VP shunt treatment (p < 0.05).Conclusions Brain tissue measurements of soluble Aβ species are feasible. Since high Aβ42 levels in cortical biopsy samples obtained in patients with iNPH indicated a poor surgical outcome, tissue levels of Aβ species may be associated with the clinical response to shunt treatment.
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| 4. |
- Abu Hamdeh, Sami, et al.
(författare)
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Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury
- 2018
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Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 28:4, s. 451-462
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Tidskriftsartikel (refereegranskat)abstract
- Deposition of amyloid-β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.
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| 5. |
- Adam, A, et al.
(författare)
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Abstracts from Hydrocephalus 2016.
- 2017
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Ingår i: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 14:Suppl 1
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Tidskriftsartikel (refereegranskat)
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| 6. |
- Agnarsdóttir, Margrét, 1970-, et al.
(författare)
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Expression of CMV protein pp65 in cutaneous malignant melanoma
- 2019
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:10
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Tidskriftsartikel (refereegranskat)abstract
- Human cytomegalovirus (CVM) has been detected by immunohistochemistry (IHC) in brain tumours; however, whether CMV antigen is seen in melanomas has not yet been elucidated. Applying IHC, melanoma tissue was assessed for the expression of pp65, a tegument protein of CMV. Two cohorts were available, cohort-I and II, the latter included also related metastasis. In addition to IHC, in situ hybridisation (ISH) was carried out to assess whether CMV related genetic sequences were detectable in a subset of cases. Seventy per cent of the 142 cases in cohort-I and 50% of the 37 cases in cohort-II displayed immunoreactivity (IR). In both cohorts, the IHC outcome correlated with T-stage (Cohort I: Spearman 0.22, p = 0.01, Cohort II: Fisher exact text 0.04). In 30 of cohort-II cases, when IHC staining was carried out on both the primary tumour and the corresponding metastasis, no change in IR was noted in 53%; in 20%, the IR was lower and in 27% higher in the metastasis when compared with the primary tumour. These results were significant (Fisher exact test 0.03). Applying ISH technique on four tumour cases with detectable pp65 protein, CMV related genetic sequence was not detected. Here, we demonstrate, congruent with observations published for brain tumours, that the protein pp65 is indeed observed in substantial number of melanoma cases with IHC; however, no signal was detected with ISH technique. These findings are in line with previously reported studies, demonstrating that the role of CMV in tumours is still debatable.
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| 7. |
- Aho, Leena, et al.
(författare)
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Beta-amyloid aggregation in human brains with cerebrovascular lesions.
- 2006
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 37:12, s. 2940-5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: The present study assessed beta-amyloid (Abeta) protein aggregates in postmortem human brains in subjects who had experienced stroke to examine the proposed association between ischemic stress and the accumulation of Abeta reported in rodents. METHODS: A sample of 484 postmortem brains from nondemented subjects, lacking isocortical neurodegenerative pathology with verified cerebrovascular lesions, and 57 age-matched controls were assessed with respect to Abeta, Abeta40, and Abeta42 aggregates in the cortex and thalamus by immunohistochemical techniques. RESULTS: The load of Abeta aggregates did not display a significant association with cerebrovascular lesions. The load of Abeta, Abeta40, and Abeta42 aggregates increased with age, and there was a tendency toward higher odds ratios for Abeta aggregates, though not statistically significant, in subjects with acute cerebrovascular lesions. In the oldest subjects with cerebrovascular lesions and with both thalamic and cortical Abeta aggregates, the load of thalamic Abeta42 was significantly higher than the load of Abeta40. CONCLUSIONS: Our findings indicate that cerebrovascular disease does not influence the load of Abeta, whereas a shift of aggregation from the Abeta40 to the Abeta42 residue is noted in the thalamus but only in aged subjects. It is impossible, however, to state whether this result is attributable to increased Abeta production, its insufficient elimination, or other susceptibility factors.
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| 8. |
- Aho, Leena, et al.
(författare)
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Heavy alcohol consumption and neuropathological lesions : a post-mortem human study
- 2009
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547. ; 87:12, s. 2786-2792
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological studies have indicated that excessive alcohol consumption leads to cognitive impairment, but the specific pathological mechanism involved remains unknown. The present study evaluated the association between heavy alcohol intake and the neuropathological hallmark lesions of the three most common neurodegenerative disorders, i.e., Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular cognitive impairment (VCI), in post-mortem human brains. The study cohort was sampled from the subjects who underwent a medicolegal autopsy during a 6-month period in 1999 and it included 54 heavy alcohol consumers and 54 age- and gender-matched control subjects. Immunohistochemical methodology was used to visualize the aggregation of beta-amyloid, hyperphosphorylated tau, and alpha-synuclein and the extent of infarcts. In the present study, no statistically significant influence was observed for alcohol consumption on the extent of neuropathological lesions encountered in the three most common degenerative disorders. Our results indicate that alcohol-related dementia differs from VCI, AD, and DLB; i.e., it has a different etiology and pathogenesis.
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| 9. |
- Aho, Leena, et al.
(författare)
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Immunohistochemical Visualization of Amyloid-β Protein Precursor and Amyloid-β in Extra- and Intracellular Compartments in the Human Brain
- 2010
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 20:4, s. 1015-1028
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta (Abeta) peptide, a cleavage product of the amyloid-beta protein precursor (AbetaPP), has been reported to be detected in the intracellular compartment. Most studies reporting the presence of intracellular Abeta are based on the use of immunohistochemistry. In this study, the presence of AbetaPP and Abeta was assessed by applying immunohistochemistry in postmortem human brain tissue samples obtained from 10 neurologically intact subjects, the youngest being 2 years of age, one aged with mild cognitive impairment, 14 neurologically diseased, and in one brain biopsy sample obtained from a subject with normal pressure hydrocephalus. Intracellular immunoreactivity was detected in all ages independent of the disease state or existence of extracellular Abeta aggregates with all antibodies directed to AbetaPP, with three Abeta antibodies (4G8, 6E10, and 82E1), clones that are unable to distinguish Abeta from AbetaPP. These results suggest that it is AbetaPP rather than Abeta that is detected intracellularly when using the antibodies listed above. Furthermore, the staining results varied when different pretreatment strategies were applied. Interestingly intracellular Abeta was detected with antibodies directed to the C-terminus of Abeta (neoepitope) in subjects with Alzheimer's disease. The lack of intracellular immunoreactivity in unimpaired subjects, when using antibodies against neoepitopes, may be due to a lack or a low level of the protein that is thus undetectable at light microscopic level by immunohistochemistry method. The staining results and conclusions depended strongly on the chosen antibody and the pretreatment strategy and thus multiple antibodies must be used when assessing the intracellular accumulation of Abeta.
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| 10. |
- 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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| 11. |
- Alafuzoff, Irina, et al.
(författare)
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Ageing-Related Neurodegeneration and Cognitive Decline
- 2024
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 25:7
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Tidskriftsartikel (refereegranskat)abstract
- Neuropathological assessment was conducted on 1630 subjects, representing 5% of all the deceased that had been sent to the morgue of Uppsala University Hospital during a 15-year-long period. Among the 1630 subjects, 1610 were ≥ 41 years of age (range 41 to 102 years). Overall, hyperphosphorylated (HP) τ was observed in the brains of 98% of the 1610 subjects, and amyloid β-protein (Aβ) in the brains of 64%. The most common alteration observed was Alzheimer disease neuropathologic change (ADNC) (56%), followed by primary age-related tauopathy (PART) in 26% of the subjects. In 16% of the subjects, HPτ was limited to the locus coeruleus. In 14 subjects (<1%), no altered proteins were observed. In 3 subjects, only Aβ was observed, and in 17, HPτ was observed in a distribution other than that seen in ADNC/PART. The transactive DNA-binding protein 43 (TDP43) associated with limbic-predominant age-related TDP encephalopathy (LATE) was observed in 565 (35%) subjects and α-synuclein (αS) pathology, i.e., Lewy body disease (LBD) or multi system atrophy (MSA) was observed in the brains of 21% of the subjects. A total of 39% of subjects with ADNC, 59% of subjects with PART, and 81% of subjects with HPτ limited to the locus coeruleus lacked concomitant pathologies, i.e., LATE-NC or LBD-NC. Of the 293 (18% of the 1610 subjects) subjects with dementia, 81% exhibited a high or intermediate level of ADNC. In 84% of all individuals with dementia, various degrees of concomitant alterations were observed; i.e., MIXED-NC was a common cause of dementia. A high or intermediate level of PART was observed in 10 subjects with dementia (3%), i.e., tangle-predominant dementia. No subjects exhibited only vascular NC (VNC), but in 17 subjects, severe VNC might have contributed to cognitive decline. Age-related tau astrogliopathy (ARTAG) was observed in 37% of the 1610 subjects and in 53% of those with dementia.
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| 12. |
- Alafuzoff, Irina, et al.
(författare)
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Alpha-synucleinopathies.
- 2017
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Ingår i: Handbook of Clinical Neurology. - 0072-9752 .- 2212-4152. ; 145, s. 339-353
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Tidskriftsartikel (refereegranskat)abstract
- A neurodegenerative disorder displaying an altered α-synuclein (αS) in the brain tissue is called α-synucleinopathy (αS-pathy) and incorporates clinical entities such as Parkinson disease (PD), PD with dementia, dementia with Lewy bodies, and multiple-system atrophy. Neuroradiologic techniques visualizing αS pathology in the brain or assays of αS in the cerebrospinal fluid or blood are probably available and will be implemented in the near future but currently the definite diagnosis of αS-pathy relies on a postmortem examination of the brain. Since the 1980s immunohistochemical technique based on the use of antibodies directed to proteins of interest has become a method of choice for neuropathologic diagnosis. Furthermore, since the 1990s it has been acknowledged that progressions of most neurodegenerative pathologies follow a certain predictable time-related neuroanatomic distribution. Currently, for Lewy body disease, two staging techniques are commonly used: McKeith and Braak staging. Thus, the neuropathologic diagnosis of a αS-pathy is based on detection of altered αS in the tissue and registration of the neuroanatomic distribution of this alteration in the brain. The clinicopathologic correlation is not absolute due to the quite frequent observation of incidental and concomitant αS pathology.
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| 13. |
- Alafuzoff, Irina
(författare)
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Alzheimerin tauti : (Alzheimer’s sjukdom)
- 2012. - 1
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Ingår i: Patologia. - Helsingfors : Duodecim. - 9789516561847 ; , s. 1029-1031
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 14. |
- Alafuzoff, Irina
(författare)
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Alzheimer's disease-related lesions
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 33:Suppl 1, s. S173-S179
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Forskningsöversikt (refereegranskat)abstract
- The invitation to contribute to "Alzheimer's Disease: Advances for a New Century" gave me an opportunity to briefly summarize my personal opinions about how the field of neuropathology has evolved. The goal is to briefly exemplify the changes that have influenced the way we conduct our diagnostic work as well as the way we interpret our results. From an era of histological stains, we have moved to visualization of altered proteins in predicted brain regions; we have also realized that in many aged subjects, not one but a plethora of co-pathologies are seen, and finally, we have become aware that the degenerative process is initiated much earlier than we ever suspected.
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| 15. |
- 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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| 16. |
- Alafuzoff, Irina, et al.
(författare)
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Assessment of beta-amyloid deposits in human brain : 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. ; 117:3, s. 309-320
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Tidskriftsartikel (refereegranskat)abstract
- beta-Amyloid (A-beta) related pathology shows a range of lesions which differ both qualitatively and quantitatively. Pathologists, to date, mainly focused on the assessment of both of these aspects but attempts to correlate the findings with clinical phenotypes are not convincing. It has been recently proposed in the same way as iota and alpha synuclein related lesions, also A-beta related pathology may follow a temporal evolution, i.e. distinct phases, characterized by a step-wise involvement of different brain-regions. Twenty-six independent observers reached an 81% absolute agreement while assessing the phase of A-beta, i.e. phase 1 = deposition of A-beta exclusively in neocortex, phase 2 = additionally in allocortex, phase 3 = additionally in diencephalon, phase 4 = additionally in brainstem, and phase 5 = additionally in cerebellum. These high agreement rates were reached when at least six brain regions were evaluated. Likewise, a high agreement (93%) was reached while assessing the absence/presence of cerebral amyloid angiopathy (CAA) and the type of CAA (74%) while examining the six brain regions. Of note, most of observers failed to detect capillary CAA when it was only mild and focal and thus instead of type 1, type 2 CAA was diagnosed. In conclusion, a reliable assessment of A-beta phase and presence/absence of CAA was achieved by a total of 26 observers who examined a standardized set of blocks taken from only six anatomical regions, applying commercially available reagents and by assessing them as instructed. Thus, one may consider rating of A-beta-phases as a diagnostic tool while analyzing subjects with suspected Alzheimer's disease (AD). Because most of these blocks are currently routinely sampled by the majority of laboratories, assessment of the A-beta phase in AD is feasible even in large scale retrospective studies.
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| 17. |
- Alafuzoff, Irina, et al.
(författare)
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Beta-amyloid deposition in brains of subjects with diabetes
- 2009
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 35:1, s. 60-68
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Tidskriftsartikel (refereegranskat)abstract
- AIM:A causative association between diabetes mellitus (DM) and Alzheimer's disease (AD) has been suggested based on clinical and epidemiological studies. One hypothesis is that the link between DM and AD is related to the function of insulin-degrading enzyme (IDE), an enzyme that degrades not only insulin and pancreatic amylin but also beta-amyloid (Abeta). Thus, in diabetics, insulin and Abeta might compete for IDE and this might lead to an increase in Abeta. The objective of this study was to test the hypothesis that hyperinsulinaemia can elevate Abeta levels and thus contribute to AD pathology in humans.METHODS:Neuropathological examination was carried out employing conventional and immunohistochemical (IHC) methods of the brains obtained post mortem from 701 aged subjects.RESULTS:The loads of IHC/Abeta, silver stained neuritic plaques (NP) and neurofibrillary tangles (NFT) were significantly higher in subjects carrying the Apolipoprotein E e4 allele. In contrast, the loads of Abeta, NPs and NFT in the brains were not influenced by hyperglycaemia when comparing 134 diabetic with 567 non-diabetic subjects.CONCLUSIONS:We conclude that the hypothesis that hyperinsulinaemia would significantly elevate the Abeta load and thus increase the extent of AD pathology cannot be supported. Our result challenges the claim that DM is a direct risk factor of developing AD. Thus further studies on pathological lesions in demented diabetics should be conducted.
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| 18. |
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| 19. |
- Alafuzoff, Irina, et al.
(författare)
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Comorbidities.
- 2017
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Ingår i: Handbook of Clinical Neurology. - 0072-9752 .- 2212-4152. ; 145, s. 573-577
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Tidskriftsartikel (refereegranskat)abstract
- The term comorbidities or mixed pathologies is used when brain tissue, a surgical sample, or postmortem brain displays a mixture of protein alterations or other pathologies. Most of the alterations when seen in sufficient extent are considered causative, are related to a certain clinical phenotype, i.e., when hyperphosphorylated τ (HPτ) is observed in occipital cortex concomitant with β-amyloid (Aβ), the diagnosis is Alzheimer disease (AD). When HPτ is observed in hippocampal structures in a subject with extensive and widespread α-synuclein pathology, a Lewy body disease (LBD), the HPτ pathology is considered as a concomitant alteration. There are numerous reports indicating that when "concomitant" pathologies are seen in a subject with certain neurodegenerative diseases, the clinical phenotype might be altered. In addition there are those cases where many alterations are seen in a sparse extent, but jointly they lead to a clinical syndrome. Thus today it is not sufficient to confirm a certain pathology to be seen, i.e., AD- or LBD-related; in addition the concomitant aging-related alterations have to be looked for.
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| 20. |
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| 21. |
- Alafuzoff, Irina, 1952-
(författare)
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Histopathological and immunocytochemical studies in age-associated dementias : the importance of rigorous histopathological criteria for classification of progressive dementia disorders
- 1985
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dementia is an age-associated organic brain disorder, recognizable by the essential features of psychological or behavioral abnormality associated with permanent dysfunction of the brain interfering with social and occupational functioning.There are two clinical and three histopathological forms of dementia 1) primary degenerative dementia, (PDD), or Alzheimer's dementia/Senile dementia of Alzheimers type (AD/SDAT) which is associated with clinical features of uniform progression and insidious onset of symptoms and histopathologically i- dentified by the occurrence of neurofibrillary tangles (NFT) and senile/neuritic plaques (SP/NP) in various cortical and subcor- tical regions; 2) vascular dementia, or multi-infarct dementia (MID), which is associated with clinical features of stepwise progress and patchy distribution of deficits, and histopathologically identified by the occurrence of multiple large and/or small haemorrhagic and/or ischaemic infarcts in various cortical and subcortical regions and 3) intermediate form of dementia or "mixed” ("combined") dementia (AD-MID), which is histopatho- logically associated with the coexistance of symptoms and lesions observed in AD/SDAT and MID, and clinically referred to the MID group. The DSM-III criteria separate the demented into two groups, AD/SDAT and MID, while there are no unique clinical criteria for the AD-MID patients. The clinical diagnosis of dementia according to the DSM-III criteria was shown to be insufficient . Histopathological diagnostic criteria were postulated by us for 1) pathological changes developing in mentallyunimpaired ageing, 2) AD/ SPAT, 3) MID and 4) AD-MID.These histopathological classes could be separated, by means of multivariate data analysis. The pathology in AD-MID was shown not to be merely a linear combination of the AD/SDATand MID pathology.Intrathecal synthesis of Ig, oligoclonal bands or other abnormal proteins in the CSF could not be demonstrated in aged non-demen- ted and demented patients.The blood-cerebrospinal barrier (B-CSF-B) or blood-brain barrier (BBB) function alters with age and this alteration was shown to be more pronounced in MID and AD-MID patients. In MID and AD-MID patients the BBB alteration involves primarily the grey matter while in AD/SDAT patients the alteration would appear to involve only the white matter. The BBB dysfunction and a possible complement activation, either through antibody-anti- gen activation or other complement activators, was visualized in MID and AD-MID patients as perivascular serum protein deposits in the grey matter, always with a capillary in the center. The occurrence of some serum proteins in plaques, and the previously descibed localization of plaques in close relationship to the capillaries, suggest that altered BBB function and serum factors may be involved in the etiology and maturation of plaques while the etiology and maturation of tangles may not be directly dependent on these factors, as they were never labelled with any of the antisera studied.
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| 22. |
- Alafuzoff, Irina, et al.
(författare)
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Inter-laboratory comparison of neuropathological assessments of beta-amyloid protein : a study of the BrainNet Europe consortium.
- 2008
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 115:5, s. 533-46
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta-protein (Abeta) is generally assessed by neuropathologists in diagnostics. This BrainNet Europe ( http://www.brainnet-europe.org/ ) (15 centres and 26 participants) study was carried out to investigate the reliability of such an assessment. In the first part of this trial, tissue microarray sections were stained with the antibody of each centre's choice. Reflecting the reality, seven antibodies and a plethora of pretreatment strategies were used. Ninety-two percent of the stainings were of good/acceptable quality and the estimation of presence of Abeta aggregates yielded good results. However, a poor agreement was reached particularly regarding quantitative (density) and qualitative (diffuse/cored plaques) results. During a joint meeting, the clone 4G8 was determined to label best the fleecy/diffuse plaques, and thus, this clone and the formic acid pretreatment technique were selected for the second part of this study. Subsequently, all stained sections were of good/acceptable quality and again a high level of concordance of the dichotomized (presence/absence) assessment of plaques and CAA was achieved. However, even when only one antibody was used, the type of Abeta-aggregates (diffuse/cored), type of vessel and Vonsattel grade, were not reliably assigned. Furthermore, the quantification of lesions was far from reliable. In line with the first trial, the agreement while assessing density (some, moderate and many) was unimpressive. In conclusion, we can confirm the utility of immunohistochemical detection of Abeta-protein in diagnostics and research. It is noteworthy that to reach reproducible results a dichotomized assessment of Abeta-immunoreactivity rather than quantification and assignment of various types of lesions should be applied, particularly when comparing results obtained by different neuropathologists.
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| 23. |
- Alafuzoff, Irina
(författare)
-
Minimal neuropathologic diagnosis for brain banking in the normal middle-aged and aged brain and in neurodegenerative disorders.
- 2018
-
Ingår i: Handbook of Clinical Neurology. - 0072-9752 .- 2212-4152. ; 150, s. 131-141
-
Tidskriftsartikel (refereegranskat)abstract
- Research on human brain diseases is currently often conducted on cell cultures and animals. Several questions however can only be addressed by studying human postmortem brain tissue. However, brain tissue obtained postmortem almost always displays pathology that is often related to the aging phenomenon. Thus, in order to be certain that the answers obtained are reliable, a systematic and thorough assessment of the brain tissue to be studied should be carried out. We are currently aware of several protein alterations that are found in middle-aged and aged brains that are obtained from neurologically unimpaired subjects. The most common alteration is hyperphosphorylation of τ, observed in both neurons and glial cells, in certain brain regions, followed by β-amyloid aggregation in the neuropil and vessel walls. Less common protein alterations are those noted for α-synuclein and Tar DNA-binding protein 43. It is noteworthy that these alterations, when found in excess, are diagnostic for various neurodegenerative diseases, such as Alzheimer disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, Parkinson disease, Lewy body dementia, and frontotemporal lobar degeneration. Since 1990, the neuropathology community has been aware that these protein alterations tend to progress in an orderly neuroanatomically defined manner and have thus designed a method to define a stage or a phase of the protein alteration. The neuropathology community has defined an initiation site, or neuroanatomic area that they presume the alteration originates from, and defined a presumed pattern of progression from the initiation site to other brain areas. Thus a reliable and reproducible description of each case regarding these alterations can be achieved. In addition to the above alterations, the brain tissue is also prone to various vascular alterations that should be registered as seen or not seen even if the significance of these alterations is still unclear.
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| 24. |
- Alafuzoff, Irina, et al.
(författare)
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Mixed Brain Pathology Is the Most Common Cause of Cognitive Impairment in the Elderly
- 2020
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Ingår i: Journal of Alzheimer's Disease. - : IOS PRESS. - 1387-2877 .- 1875-8908. ; 78:1, s. 453-465
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Systemic diseases, diabetes mellitus (DM), and cardiovascular disease (CaVD) have been suggested being risk factors for cognitive impairment (CI) and/or influence Alzheimer's disease neuropathologic change (ADNC).Objective: The purpose was to assess the type and the extent of neuropathological alterations in the brain and to assess whether brain pathology was associated with CaVD or DM related alterations in peripheral organs, i.e., vessels, heart, and kidney.Methods: 119 subjects, 15% with DM and 24% with CI, age range 80 to 89 years, were chosen and neuropathological alterations were assessed applying immunohistochemistry.Results: Hyperphosphorylated tau (HP tau) was seen in 99%, amyloid-beta (A beta) in 71%, transactive DNA binding protein 43 (TDP43) in 62%, and alpha-synuclein (alpha S) in 21% of the subjects. Primary age related tauopathy was diagnosed in 29% (more common in females), limbic predominant age-related TDP encephalopathy in 4% (14% of subjects with CI), and dementia with Lewy bodies in 3% (14% of subjects with CI) of the subjects. High/intermediate level of ADNC was seen in 47% and the extent of HPt increased with age. The extent of ADNC was not associated with the extent of pathology observed in peripheral organs, i.e., DM or CaVD. Contrary, brain alterations such as pTDP43 and cerebrovascular lesions (CeVL) were influenced by DM, and CeVL correlated significantly with the extent of vessel pathology.Conclusion: In most (66%) subjects with CI, the cause of impairment was "mixed pathology", i.e., ADNC combined with TDP43, alpha S, or vascular brain lesions. Furthermore, our results suggest that systemic diseases, DMand CaVD, are risk factors for CI but not related to ADNC.
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| 25. |
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| 26. |
- Alafuzoff, Irina, et al.
(författare)
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Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions : an inter-laboratory study by the BrainNet Europe consortium
- 2015
-
Ingår i: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 122:7, s. 957-972
-
Tidskriftsartikel (refereegranskat)abstract
- The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.
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| 27. |
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| 28. |
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| 29. |
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| 30. |
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| 31. |
- Alafuzoff, Irina, et al.
(författare)
-
Staged pathology in Parkinson's disease
- 2014
-
Ingår i: Parkinsonism & Related Disorders. - 1353-8020 .- 1873-5126. ; 20:Suppl. 1, s. S57-S61
-
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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| 32. |
- Alafuzoff, Irina, et al.
(författare)
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Staging of neurofibrillary pathology in Alzheimer's disease : a study of the BrainNet Europe Consortium.
- 2008
-
Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 18:4, s. 484-96
-
Tidskriftsartikel (refereegranskat)abstract
- It has been recognized that molecular classifications will form the basis for neuropathological diagnostic work in the future. Consequently, in order to reach a diagnosis of Alzheimer's disease (AD), the presence of hyperphosphorylated tau (HP-tau) and beta-amyloid protein in brain tissue must be unequivocal. In addition, the stepwise progression of pathology needs to be assessed. This paper deals exclusively with the regional assessment of AD-related HP-tau pathology. The objective was to provide straightforward instructions to aid in the assessment of AD-related immunohistochemically (IHC) detected HP-tau pathology and to test the concordance of assessments made by 25 independent evaluators. The assessment of progression in 7-microm-thick sections was based on assessment of IHC labeled HP-tau immunoreactive neuropil threads (NTs). Our results indicate that good agreement can be reached when the lesions are substantial, i.e., the lesions have reached isocortical structures (stage V-VI absolute agreement 91%), whereas when only mild subtle lesions were present the agreement was poorer (I-II absolute agreement 50%). Thus, in a research setting when the extent of lesions is mild, it is strongly recommended that the assessment of lesions should be carried out by at least two independent observers.
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| 33. |
- 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
-
Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 117:6, s. 635-652
-
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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| 34. |
- Alafuzoff, Irina, et al.
(författare)
-
Synucleinopathies
- 2015
-
Ingår i: Neuropathology of neurodegenerative diseases. - : Cambridge University Press. - 9781107588660 - 9781107674202 ; , s. 149-175
-
Bokkapitel (refereegranskat)abstract
- Definition, structure and biochemical background Similar to other “proteinopathies,” the process that links α-synuclein (αS) protein to disease pathogenesis originated from the discovery that a single point mutation in the αS gene (i.e. SNCA) can cause autosomal-dominant Parkinson’s disease (PD) [1]. This was followed by the breakthrough finding that the actual transcribed protein was a major fibrillar component of pathological hallmarks known as Lewy bodies (LBs), Lewy neurites (LNs) and glial cytoplasmic inclusions characterizing a heterogeneous group of diseases, now collectively referred to as “synucleinopathies,” i.e. PD, PD with dementia (PDD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) [2, 3]. Currently, there are five missense mutations (pA53T, p.A30P, p.E46K, p.H50Q and p.G51D) [1, 4–8] and multiplication mutations (SNCA duplication and triplication) [9–11] that are genetically linked to clinical parkinsonism (Table 9.1). This genetic and pathological linkage establishes αS as an important player in the development of these disorders.
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| 35. |
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| 36. |
- Alafuzoff, Irina
(författare)
-
Techniques in neuropathology.
- 2017
-
Ingår i: Handbook of Clinical Neurology. - 0072-9752 .- 2212-4152. ; 145, s. 3-7
-
Tidskriftsartikel (refereegranskat)abstract
- The primary objective for a neuropathologist is the characterization of the tissue that is being assessed and thus all available techniques ranging from naked-eye examination to assessment of genetic/epigenetic characteristics are currently applied. What is observed in the tissue obtained from a diseased subject is compared with what is observed in a healthy individual and, based on the outcome, neuropathologic definitions of diseases are constructed. Thus, with the naked eye a neuropathologist can confirm that a hemorrhage is observed in the brain, by histologic examination that the hemorrhage is caused by alterations in the brain vessels and, since 1954, applying Congo red dye neuropathologists have been able to state that congophilic angiopathy is detected. Since 1984, applying immunohistochemical methods neuropathologists have been able to verify that the protein seen in the vessel walls is β-amyloid and by genetic/epigenetic analysis eventual mutation or modifications of genome might be detected. The development of new techniques is staggering and throughout this book the authors have listed techniques currently applied while assessing various disease-related hallmark lesions. In the following a general summary of techniques applied is given.
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| 37. |
- Alafuzoff, Irina, et al.
(författare)
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The need to unify neuropathological assessments of vascular alterations in the ageing brain : Multicentre survey by the BrainNet Europe consortium
- 2012
-
Ingår i: Experimental Gerontology. - : Elsevier BV. - 0531-5565 .- 1873-6815. ; 47:11, s. 825-833
-
Tidskriftsartikel (refereegranskat)abstract
- Here, we summarise the results after carrying out a large survey regarding the assessment of vascular alterations, both vessel changes and vascular lesions in an inter-laboratory setting. In total, 32 neuropathologists from 22 centres, most being members of BrainNet Europe (BNE), participated by filling out a questionnaire with emphasis on assessment of common vascular alterations seen in the brains of aged subjects. A certain level of harmonisation has been reached among BNE members regarding sectioning of the brain, harvesting of brain tissue for histology and staining used when compared to the survey carried out in 2006 by Pantoni and colleagues. The most significant variability was seen regarding the assessment of severity and of clinical significance of vascular alterations. Two strategies have recently been recommended regarding the assessment of vascular alterations in aged and demented subjects. The National Institute on Aging - Alzheimer's Association (NIA-AA) recommends the assessment of hippocampal sclerosis, vascular brain injury and microvascular lesions in 12 regions. Although this strategy will be easy to follow, the recommendations do not inform how the load of observed alterations should be assessed and when the observed lesions are of significance. Deramecourt and his colleagues recommend an assessment and semiquantitative grading of various pathologies in 4 brain regions. This strategy yielded a total score of 0 to 20 as an estimate of pathology load. It is, however, not clear which score is considered to be of clinical significance. Furthermore, in several BNE trials the semiquantitative assessment has yielded poor agreement rates; an observation that might negatively influence the strategy proposed by Deramecourt and his colleagues. In line with NIA-AA, a dichotomised approach of easily recognisable lesions in a standardised set of brain regions harvested for neuropathological assessment and applying reproducible sampling and staining strategies is recommended by BNE. However, a simple strategy regarding assessment of load of alteration is urgently needed to yield reproducible, and at the same time, comparable results between centres.
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| 38. |
- Amirian, E. Susan, et al.
(författare)
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The Glioma International Case-Control Study : A Report From the Genetic Epidemiology of Glioma International Consortium
- 2016
-
Ingår i: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 183:2, s. 85-91
-
Tidskriftsartikel (refereegranskat)abstract
- Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions.
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| 39. |
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| 40. |
- Axelsson, Karin, et al.
(författare)
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Nutritional status in patients with acute stroke
- 1988
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Ingår i: Acta Medica Scandinavica. - : Wiley. - 0001-6101. ; 224:3, s. 217-224
-
Tidskriftsartikel (refereegranskat)abstract
- By measuring three anthropometric variables (relative weight, triceps skinfold thickness and arm muscle circumference) and three circulating proteins (albumin, transferrin and prealbumin), nutritional status was assessed in 100 consecutive patients with acute stroke. On admission to hospital, two or more indicators showed subnormal values for 16%; this was associated with the female sex, high age and a history of atrial fibrillation. At discharge, 22% had two or more subnormal indicators. Poor nutritional status during the hospital stay appeared to be related to infections, the male sex, the intake of cardiovascular drugs and high age. Fewer of the patients with two or more subnormal nutritional indicators were able to return home than of the patients with none or one subnormal nutritional indicator. We conclude that undernutrition is not uncommon at the onset of stroke and that certain risk groups for the development of undernutrition during hospital stay can be identified.
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| 41. |
- Bell, Jeanne E, et al.
(författare)
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Management of a twenty-first century brain bank : experience in the BrainNet Europe consortium.
- 2008
-
Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 115:5, s. 497-507
-
Tidskriftsartikel (refereegranskat)abstract
- Collections of human postmortem brains gathered in brain banks have underpinned many significant developments in the understanding of central nervous system (CNS) disorders and continue to support current research. Unfortunately, the worldwide decline in postmortem examinations has had an adverse effect on research tissue procurement, particularly from control cases (non-diseased brains). Recruitment to brain donor programmes partially addresses this problem and has been successful for dementing and neurodegenerative conditions. However, the collection of brains from control subjects, particularly from younger individuals, and from CNS disorders of sudden onset, remains a problem. Brain banks need to adopt additional strategies to circumvent such shortages. The establishment of brain bank networks allows data on, and access to, control cases and unusual CNS disorders to be shared, providing a larger resource for potential users. For the brain banks themselves, inclusion in a network fosters the sharing of protocols and development of best practice and quality control. One aspect of this collective experience concerns brain bank management, excellence in which is a prerequisite not only for gaining the trust of potential donors and of society in general, but also for ensuring equitable distribution to researchers of high quality tissue samples. This review addresses the legal, ethical and governance issues, tissue quality, and health and safety aspects of brain bank management and data management in a network, as well as the needs of users, brain bank staffing, donor programs, funding issues and public relations. Recent developments in research methodology present new opportunities for researchers who use brain tissue samples, but will require brain banks to adopt more complex protocols for tissue collection, preparation and storage, with inevitable cost implications for the future.
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| 42. |
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| 43. |
- Buerger, Katharina, et al.
(författare)
-
CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease.
- 2006
-
Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 129:Pt 11, s. 3035-41
-
Tidskriftsartikel (refereegranskat)abstract
- Hyperphosphorylated tau protein (P-tau) in CSF is a core biomarker candidate of Alzheimer's disease. Hyperphosphorylation of tau is thought to lead to neurofibrillary changes, a neuropathological hallmark of this type of dementia. Currently, the question is unresolved whether CSF levels of P-tau reflect neurofibrillary changes within the brain of a patient with the illness. Twenty-six patients were included with intra-vitam CSF as well as post-mortem neuropathological data. In the CSF, P-tau phosphorylated at threonine 231 (P-tau231P) was analysed. Post-mortem, scores of neurofibrillary tangles (NFT) and neuritic plaques (NP) were assessed in frontal, temporal, parietal and hippocampal cortical areas. In the same cortical regions, load of hyperphosphorylated tau protein (HP-tau load) was determined. Concentrations of P-tau231P were measured in frontal cortex homogenates. We found significant correlations between CSF P-tau231P concentrations and scores of NFTs and HP-tau load in all neocortical regions studied. The score of NPs was correlated with CSF P-tau231P only within the frontal cortex. There was a correlation between P-tau231P in CSF and brain homogenates. These findings indicate that CSF P-tau231P may serve as an in vivo surrogate biomarker of neurofibrillary pathology in Alzheimer's disease.
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| 44. |
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| 45. |
- Caglayan, Demet, et al.
(författare)
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Induction of Glioblastoma Multiforme and Gliomatosis Cerebri with a Sleeping Beauty gene transfer system, implications for T regulatory cell involvement during glioma formation.
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma Multiforme (GBM), the most malignant and common neoplasm of the central nervous system (CNS), has been classified into subgroups with gene-expression profile as the basis for categorization. Among these the mesenchymal subgroup is most greatly associated with inflammatory infiltrates and increased expression of inflammatory associated genes. GBMs exhibit T cell infiltration to a varying degree and today the degree of infiltration is not used in prognostics. The Sleeping Beauty (SB) system was used to introduce AKT, a mutant variant of NRAS and a shp53 coupled to green fluorescent protein (GFP) into mice that are fully immunocomptetent, lack mature T cells or have reduced regulatory T (Treg) cell function respectively. We report, for the first time, the induction of Gliomatosis Cerebri with the SB system. Tumors that originated were either GBM or Gliomatosis Cerebri with a similar incidence. There was no difference in survival, grade or incidence of induced tumors in wild type mice and mice that lack mature T cells.
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| 46. |
- Casar-Borota, Olivera, et al.
(författare)
-
Expression of SSTR2a, but not of SSTRs 1, 3, or 5 in Somatotroph Adenomas Assessed by Monoclonal Antibodies Was Reduced by Octreotide and Correlated With the Acute and Long-Term Effects of Octreotide
- 2013
-
Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 98:11, s. E1730-E1739
-
Tidskriftsartikel (refereegranskat)abstract
- Context: Reduced expression of somatostatin receptors (SSTRs) in somatotroph adenomas and their potential down-regulation after medical treatment may explain the unsatisfactory response to octreotide in particular acromegalic patients. The expression of SSTRs other than SSTR2a has not been studied in large, unselected cohorts using novel rabbit monoclonal antibodies. Objective: We aimed to determine the expression of SSTRs 1, 2a, 3, and 5 in somatotroph adenomas, to correlate expression with clinical characteristics and the response to octreotide, and to ascertain whether preoperative octreotide treatment affected SSTR expression. Design, Setting, Patients: The study included 78 adenomas from patients operated on consecutively during 2000 to 2010. After exclusion of 13 patients, immunohistochemical analysis with rabbit monoclonal antibodies against SSTRs 1, 2a, 3, and 5 (clones UMB-7, -1, -5, and -4) was performed on 65 adenomas. Intervention: Twenty-eight patients received preoperative octreotide, and 37 patients were operated on without pretreatment. Twenty-six patients were randomized to direct surgery (n = 13) or to octreotide pretreatment (n = 13). Main Outcome Measure: SSTR expression was evaluated using a 12-grade scoring system. The responses to the octreotide test dose (GH reduction) and to 6 months of octreotide (IGF-I reduction) were measured. Results: The majority of adenomas showed membranous expression of SSTRs 2a and 5. SSTR2a expression was reduced in the pretreated group and correlated with the acute octreotide test results and the effect of octreotide treatment. In a linear regression model with SSTR2 a expression as the determinant, the correlation with the acute test response improved after adjustment for medical pretreatment. Conclusion: Rabbit monoclonal antibodies are reliable markers of SSTRs in somatotroph adenomas. SSTR2a expression correlated with the response to octreotide and was reduced after octreotide treatment, indicating the need for adjustment when SSTR2a expression is correlated with baseline characteristics. Evaluation of SSTR subtypes may be an important aspect of improving the medical treatment for acromegaly.
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| 47. |
- Crary, John F., et al.
(författare)
-
Primary age-related tauopathy (PART) : a common pathology associated with human aging
- 2014
-
Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 128:6, s. 755-766
-
Tidskriftsartikel (refereegranskat)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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| 48. |
- de la Vega, Maria Pagnon, et al.
(författare)
-
The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid beta fibril formation
- 2021
-
Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 13:606
-
Tidskriftsartikel (refereegranskat)abstract
- Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid beta (A beta). Here, we describe the Uppsala APP mutation (Delta 690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) A beta 42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing beta-secretase cleavage and affecting alpha-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated A beta, A beta Upp1-42(Delta 19-24), accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.
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| 49. |
- Dieterich, Lothar C., et al.
(författare)
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Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization
- 2012
-
Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 228:3, s. 378-390
-
Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma are aggressive astrocytic brain tumours characterized by microvascular proliferation and an abnormal vasculature, giving rise to brain oedema and increased patient morbidity. Here, we have characterized the transcriptome of tumour-associated blood vessels and describe a gene signature clearly associated with pleomorphic, pathologically altered vessels in human glioblastoma (grade IV glioma). We identified 95 genes differentially expressed in glioblastoma vessels, while no significant differences in gene expression were detected between vessels in non-malignant brain and grade II glioma. Differential vascular expression of ANGPT2, CD93, ESM1, ELTD1, FILIP1L and TENC1 in human glioblastoma was validated by immunohistochemistry, using a tissue microarray. Through qPCR analysis of gene induction in primary endothelial cells, we provide evidence that increased VEGF-A and TGFβ2 signalling in the tumour microenvironment is sufficient to invoke many of the changes in gene expression noted in glioblastoma vessels. Notably, we found an enrichment of Smad target genes within the distinct gene signature of glioblastoma vessels and a significant increase of Smad signalling complexes in the vasculature of human glioblastoma in situ. This indicates a key role of TGFβ signalling in regulating vascular phenotype and suggests that, in addition to VEGF-A, TGFβ2 may represent a new target for vascular normalization therapy.
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| 50. |
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