Sofie Ingvast

Frontotemporal dementia-amyotrophic lateral sclerosis complex is simulated by neurodegeneration with brain iron accumulation.

We describe a case of late onset neurodegeneration with brain iron accumulation (NBIA) presenting as frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS). A male patient presented at age 66 with change of personality: disinhibition, emotional blunting, and socially inappropriate behavior, coupled with dysarthria, dystonia, and corticospinal tract involvement. Magnetic resonance imaging showed general cortical atrophy, iron deposits in the globus pallidus, and the “eye of the tiger” sign. Neuropsychologic performance was globally reduced, especially executive functions. Fluorodeoxyglucose positron emission tomography showed hypometabolism predominantly in frontal and temporal areas. Repeated neurophysiologic examinations showed signs of chronic denervation. The patient was diagnosed with NBIA but fulfilled consensus criteria for FTD and had a clinical picture of ALS, without neurophysiologic confirmation. Our finding introduces NBIA as a possible cause of FTD and as a differential diagnosis of the FTD-ALS complex.

Characterization of human organ donors testing positive for type 1 diabetes‐associated autoantibodies

In this study we aim to describe the characteristics of non‐diabetic organ donors with circulating diabetes‐associated autoantibodies collected within the Nordic Network for Islet Transplantation. One thousand and thirty organ donors have been screened in Uppsala for antibodies against glutamic acid decarboxylase (GADA) and islet antigen‐2 (IA‐2A). The 32 non‐diabetic donors that tested positive for GADA (3·3% of all non‐diabetic donors) were studied in more detail, together with 32 matched controls. Mean age among the autoantibody‐positive donors was 52·6 (range 21–74), family history of type 1 diabetes (T1D) was unknown, and no donor was genetically predisposed for T1D regarding the human leucocyte antigen (HLA) locus. Subjects were analysed for islet cell antibodies (ICA), insulin autoantibodies (IAA) and zinc transporter 8 antibodies (ZnT8A), and pancreas morphology and clinical data were examined. Eight non‐diabetic donors tested positive for two antibodies and one donor tested positive for four antibodies. No insulitis or other signs of a diabetic process were found in any of the donors. While inflammatory cells were present in all donors, subjects with high GADA titres had significantly higher CD45 cell numbers in exocrine tissue than controls. The extent of fibrosis was more pronounced in autoantibody‐positive donors, even in subjects with lower GADA titres. Notably, it is possible that events not related directly to T1D (e.g. subclinical pancreatitis) may induce autoantibodies in some cases.

New Alzheimer’s disease locus on chromosome 8

Background: Family history is one of the most consistent risk factors for dementia. Therefore, analysis of families with a distinct inheritance pattern of disease can be a powerful approach for the identification of previously unknown disease genes. Objective: To map susceptibility regions for Alzheimer’s disease. Methods: A complete genome scan with 369 microsatellite markers was carried out in 12 extended families collected in Sweden. Age at disease onset ranged from 53 to 78 years, but in 10 of the families there was at least one member with age at onset of ⩽65 years. Mutations in known early-onset Alzheimer’s disease susceptibility genes have been excluded. All people were genotyped for APOE, but no clear linkage with the ε4 allele was observed. Results: Although no common disease locus could be found in all families, in two families an extended haplotype was identified on chromosome 8q shared by all affected members. In one of the families, a non-parametric multimarker logarithm of the odds (LOD) score of 4.2 (p = 0.004) was obtained and analysis based on a dominant model showed a parametric LOD score of 2.4 for this region. All six affected members of this family shared a haplotype of 10 markers spanning about 40 cM. Three affected members in another family also shared a haplotype in the same region. Conclusion: On the basis of our data, we propose the existence of a dominantly acting Alzheimer’s disease susceptibility locus on chromosome 8.

Insulitis in human diabetes: a histological evaluation of donor pancreases

Aims/hypothesisAccording to the consensus criteria developed for type 1 diabetes, an individual can be diagnosed with insulitis when ≥ 15 CD45+ cells are found within the parenchyma or in the islet–exocrine interface in ≥ 3 islets. The aim of this study was to determine the frequency of individuals with type 2 diabetes fulfilling these criteria with reference to non-diabetic and type 1 diabetic individuals.MethodsInsulitis was determined by examining CD45+ cells in the pancreases of 50, 13 and 44 organ donors with type 2 diabetes, type 1 diabetes and no diabetes, respectively. CD3+ cells (T cells) infiltrating the islets were evaluated in insulitic donors. In insulitic donors with type 2 diabetes, the pancreases were characterised according to the presence of CD68 (macrophages), myeloperoxidase (MPO; neutrophils), CD3, CD20 (B cells) and HLA class I hyperstained islets. In all type 2 diabetic donors, potential correlations of insulitis with dynamic glucose-stimulated insulin secretion in vitro or age, BMI, HbA1c or autoantibody positivity were examined.ResultsOverall, 28% of the type 2 diabetic donors fulfilled the consensus criteria for insulitis developed for type 1 diabetes. Of the type 1 diabetic donors, 31% fulfilled the criteria. None of the non-diabetic donors met the criteria. Only type 1 diabetic donors had ≥ 15 CD3+ cells in ≥ 3 islets. Type 2 diabetic donors with insulitis also had a substantial number of CD45+ cells in the exocrine parenchyma. Macrophages constituted the largest fraction of CD45+ cells, followed by neutrophils and T cells. Of type 2 diabetic pancreases with insulitis, 36% contained islets that hyperstained for HLA class I. Isolated islets from type 2 diabetic donors secreted less insulin than controls, although with preserved dynamics. Insulitis in the type 2 diabetic donors did not correlate with glucose-stimulated insulin secretion, the presence of autoantibodies, BMI or HbA1c.Conclusions/interpretationThe current definition of insulitis cannot be used to distinguish pancreases retrieved from individuals with type 1 diabetes from those with type 2 diabetes. On the basis of our findings, we propose a revised definition of insulitis, with a positive diagnosis when ≥ 15 CD3+ cells, not CD45+ cells, are found in ≥ 3 islets.

No evidence of PGRN or MAPT gene dosage alterations in a collection of patients with frontotemporal lobar degeneration.

Background/Aims: Alterations in gene dosage have recently been associated with neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, and deletions of the progranulin (PGRN) locus were recently described in patients with frontotemporal lobar degeneration (FTLD). FTLD is a genetically complex neurodegenerative disorder with mutations in the PGRN and the microtubule-associated protein tau (MAPT) genes being the most common known causes of familial FTLD. In this study, we investigated 39 patients with FTLD, previously found negative for mutations in PGRN and MAPT, for copy number alterations of these 2 genes. Methods: Gene dosage analysis of PGRN and MAPT was performed using multiplex ligation-dependent probe amplification. Results: We did not identify any PGRN or MAPT gene dosage variations in the 39 FTLD patients investigated. Conclusion: We therefore conclude that alterations in gene copy number of PGRN and MAPT are not a cause of disease in this collection of FTLD patients.

Human islet isolation processing times shortened by one hour : minimized incubation time between tissue harvest and islet purification

Human Islet Isolation Processing Times Shortened By One Hour : Minimized Incubation Time Between Tissue Harvest and Islet Purification

Evaluation of RT-PCR and immunohistochemistry as tools for detection of enterovirus in the human pancreas and islets of Langerhans

BACKGROUND Enteroviruses have been implicated in the etiology of type 1 diabetes, supported by immunoreactivity of enteroviral protein in islets, but presence of enteroviral genome has rarely been reported. Failure to detect enterovirus with RT-PCR has been attributed to the possible presence of PCR inhibitors and that only few cells are infected. OBJECTIVES The aim of this study was to evaluate strategies for detection of enterovirus in human islets. STUDY DESIGN A scenario was modeled with defined infected islets among a large number of uninfected pancreatic cells and the sensitivity of immunohistochemistry and PCR for detection of enterovirus was evaluated. RESULTS Enterovirus was detected with PCR when only one single human islet, infected in vitro with a low dose of virus, was mixed with an uninfected pancreatic biopsy. Enterovirus could not be detected by immunohistochemistry under the same conditions, demonstrating the superior sensitivity of PCR also in pancreatic tissue with only a small fraction of infected cells. In addition, we demonstrate that pancreatic cell culture supernatant does not cause degradation of enterovirus at 37°C, indicating that under normal culture conditions released virus is readily detectable. Utilizing PCR, the pancreases of two organ donors that died at onset of type 1 diabetes were found negative for enterovirus genome despite islet cells being positive using immunohistochemistry. CONCLUSIONS These data suggest that PCR should be the preferred screening method for enterovirus in the pancreas and suggest cautious interpretation of immunostaining for enterovirus that cannot be confirmed with PCR.

Protein Kinase R Is Constitutively Expressed in the Human Pancreas

Summary Viral infection of the insulin-producing cells in the pancreas has been proposed in the etiology of type 1 diabetes. Protein kinase R (PKR) is a cytoplasmic protein activated through phosphorylation in response to cellular stress and particularly viral infection. As PKR expression in pancreatic beta-cells has been interpreted as a viral footprint, this cross-sectional study aimed at characterizing the PKR expression in non-diabetic human pancreases. PKR expression was evaluated in pancreas tissue from 16 non-diabetic organ donors, using immunohistochemistry, qPCR, and western blot. Immunohistochemistry and western blot showed readily detectable PKR expression in the pancreatic parenchyma. The qPCR detected PKR mRNA in both endocrine and exocrine samples, with a slightly higher expression in the islets. In conclusion, PKR is constitutively expressed in both endocrine and exocrine parts of the pancreas and its expression should not be interpreted as a viral footprint in pancreatic beta cells.

Re-addressing the 2013 consensus guidelines for the diagnosis of insulitis in human type 1 diabetes: is change necessary? Reply to Campbell-Thompson ML, Atkinson MA, Butler AE et al [letter]

Re-addressing the 2013 consensus guidelines for the diagnosis of insulitis in human type 1 diabetes : is change necessary? Reply to Campbell-Thompson ML, Atkinson MA, Butler AE et al [letter].

Seeding of cross linked alpha-synuclein oligomers in vitro and in vivo

We evaluated the correlation between each fractional anisotrophy (FA) and depression scores. Methods: Nineteen SIVD patients underwent DTI. Total 30 ROIs were measured. We conducted the correlation analysis between the depression scores FA in each 30 ROI. Results: In SIVD patients, there is a tendency of lower values of FA in the posterior body of the corpus callosum as the depression scores are getting higher.(r 1⁄4 -0.462, p < 0.05) On the other hand, there is a tendency of higher values of FA in the left temporal white matter region as the depression scores are getting higher.(r 1⁄4 0.456, p < 0.05) Conclusions: Lower FA of posterior body of the corpus callosum might imply underlying structural abnormalities that contribute to the depressive mood in SIVD patients. Higher FA of left temporal region might cause depressive mood. However, the exact mechanism how the higher left temporal FA correlates with depressive mood is not elucidated. Further large scale study should be followed to determine the roles of altered FA values in the corpus callosum and left temporal area in the pathogenesis of depression mood.