Amyloid diseases at old age : a pathological, epidemiological, and genetic study

Along with the increased life span of individuals, the burden of old age-associated diseases has inevitably increased. Alzheimer s disease (AD), probably the most well known geriatric disease, belongs to the old age-associated amyloid diseases. The purpose of this study was to investigate the frequency, genetic and health-associated risk factors, mutual association, and amyloid proteins in two old age-associated amyloid disorders senile systemic amyloidosis (SSA) and cerebral amyloid angiopathy (CAA) as part of the prospective population-based Vantaa 85+ autopsy study on a Finnish population aged 85 years or more (Studies I-III), completed with a case report on a patient with advanced AGel amyloidosis (Study IV). The numbers of patients investigated in the studies (I-III) were 256, 74, and 63, respectively. The diagnosis and grading of amyloid were based upon histological examination of tissue samples obtained post mortem and stained with Congo red. The amyloid fibril and associated proteins were characterized by immunohistochemical staining methods. The genotype frequencies of 20 polymorphisms in 9 genes and information on health-associated risk factors in subjects with and without SSA and CAA were compared. In a Finnish population ≥ 95 years of age, SSA and CAA occurred in 36% and 49% of the subjects, respectively. In total, two-thirds of these very elderly individuals had SSA, CAA, or both. However, in only 14% of the population these two conditions co-occurred. In subjects 85 years or older, the prevalence of SSA was 25%. In this population, SSA was associated with age at the time of death (p=0.002), myocardial infarctions (MIs; p=0.004), the G/G (Val/Val) genotype of the exon 24 polymorphism in the alpha2-macroglobulin (α2M) gene (p=0.042) and with the H2 haplotype of the tau gene (p=0.016). In contrast, the presence of CAA was strongly associated with APOE e4 (p=0.0003), with histopathological AD (p=0.0005), and with clinical dementia (p=0.01) in both e4+ (p=0.02) and e4- (p=0.06) individuals. Apart from demonstrating the amyloid fibril proteins, complement proteins 3d (C3d) and 9 (C9) were detected in the amyloid deposits of CAA and AGel amyloidosis, and α2M protein was found in fibrous scar tissue close to SSA. In conclusion, this first population based study on SSA shows that both SSA and CAA are common in very elderly individuals. Old age, MIs, the exon 24 polymorphism of the α2M gene, and H1/H2 polymorphism of the tau gene associate with SSA while clinical dementia and APOE ε4 genotype associate with CAA. The high prevalence of CAA, combined with its association with clinical dementia independent of APOE genotype, neuropathological AD, or SSA, also highlights its clinical significance in the very aged, among which the serious end stage complications of CAA, namely multiple infarctions and hemorrhages, are rare. The report on a patient having advanced AGel amyloidosis added knowledge on the disease and showed that this generally benign condition occasionally may lead to death. Further studies are warranted to confirm the findings in other populations. Also, the role of α2M and tau in the pathogenesis of SSA and the involvement of complement in the process of amyloid beta (Aβ) protein elimination from the brain remain to be clarified. Finally, the high prevalence of SSA in the elderly raises the need for prospective clinical studies to define its clinical significance.Teollistuneissa länsimaissa ihmisen odotettavissa oleva elinikä nousee jatkuvasti ja ikääntymiseen liittyvien sairauksien lääketieteellinen ja sosiaalis-taloudellinen merkitys lisääntyy. Ikääntymiseen liittyvistä sairauksista varmaankin tunnetuin on Alzheimerin tauti (Alzheimer s disease; AD), joka samalla on eräs ikääntymiseen liittyvistä amyloidisairauksista. Amyloidilla tarkoitetaan kudokseen liukenemattomiksi säikeiksi saostunutta valkuaisainetta. Tutkimuksessa on selvitetty kahteen vähemmän tunnettuun ikääntymiseen liittyvään amyloidisairauteen (ikääntymiseen liittyvä amyloidoosi; senile systemic amyloidosis = SSA, sekä aivojen amyloidiangiopatia; cerebral amyloid angiopathy = CAA) liittyviä epidemiologisia, histopatologisia ja geneettisiä piirteitä osana väestöpohjaista, etenevää Vantaa 85+ tutkimusta (osatyöt I-III), täydennettynä tapausselostuksella vaikeaa suomalaista perinnöllistä gelsoliiniamyloidoosia (AGel amyloidoosi) sairastaneesta potilaasta (osatyö IV). Tutkittavien lukumäärä osatöissä I-III oli 256, 74, ja 63. Amyloidoosin esiintyvyys, sen laatu ja vaikeusaste määritettiin ruumiinavauksen yhteydessä saaduista kudosnäytteistä histologisten ja immunohistokemiallisten värjäysten avulla. 20 eri geenipolymorfismin (geenin monimuotoisuus; saman geenilokuksen kahden tai useamman vaihtoehtoisen muodon esiintyminen väestössä) sekä terveyteen liittyvien riskitekijöiden (esim. diabetes, kohonnut verenpaine) esiintymistä eri väestöryhmien (SSA+, SSA-, CAA+, CAA-) välillä vertailtiin tilastollisin menetelmin. 95 -vuotiallla tai iäkkäämmillä SSA todettiin 36%:ssa ja CAA 49%:ssa väestöstä. SSA ja CAA esiintyivät samalla henkilöllä yhtäaikaisesti erittäin harvoin (14%), kun taas 2/3:lla oli joko SSA tai CAA. 85 -vuotiailla tai iäkkäämmillä SSA tavattiin 25%:lla. SSA assosioitui merkitsevästi kuolinikään, sydäninfarktien esiintymiseen, alpha2-makroglobuliini (α2M) geenin G/G polymorfismiin sekä tau geenin H2 haploptyyppiin. Sen sijaan CAA assosioitui vahvasti APOE ε4 alleeliin, neuropatologisten kriteerien mukaan määriteltyyn ADin sekä kliiniseen dementiaan. Kliiniseen dementian ja CAAn välinen assosiaatio ei ollut riippuvainen APOE genotyypistä eikä ADn neuropatologisista löydöksistä. Lisäksi havaittiin ensimmäisen kerran komplementtiproteiineja 3d ja 9 sekä CAAan että suomalaiseen amyloidoosiin liittyvissä amyloidikertymissä. Tämä ensimmäinen SSAan kohdistunut väestöpohjainen tutkimus osoittaa, että sekä SSA että CAA ovat erittäin yleisiä iäkkäillä henkilöillä. Korkea ikä, sydäninfarktien esiintyminen, ja α2M ja tau geenin polymorfismit liittyvät SSA:an, kun taas APOE -genotyyppi ja kliininen dementia (ei pelkästään AD) liittyvät CAAan. CAAn ja dementian välinen yhteys osoittaa, että CAA on kliinisesti merkityksellinen myös erittäin iäkkäillä, joilla CAAn paremmin tunnetut, vaaralliset komplikaatiot (aivoverenvuodot ja pienet pinnalliset aivoinfarktit, jotka yleensä esiintyvät hieman nuoremmilla) eivät enää ole merkittävä kliininen ongelma. Tutkimuksessa todettiin myös, että suomalainen amyloidoosi, jonka kliininen taudinkuva yleensä on lievä, saattaa joissakin tapauksissa johtaa kuolemaan. Koska SSA osoittautui iäkkäässä väestössä yleiseksi, on sen kliininen merkitys tässä ikäryhmässä syytä selvittää

Low trypsinogen-1 expression in pediatric ulcerative colitis patients who undergo surgery

Peer reviewe

Population-based analysis of pathological correlates of dementia in the oldest old

Objective: The aim of this study was to analyze brain pathologies which cause dementia in the oldest old population. Methods: All 601 persons aged >= 85 years living in the city of Vantaa (Finland), on April 1st, 1991 formed the study population of the Vantaa85 + study, 300 of whom were autopsied during follow-up (79.5% females, mean age-at-death 92 +/- 3.7 years). Alzheimer's disease (AD) pathology (tau and beta-amyloid [Ab]), cerebral amyloid angiopathy (CAA) and Lewy-related pathologies were analyzed. Brain infarcts were categorized by size ( 15 mm) and by location. Brain hemorrhages were classified as microscopic ( 2 mm cortical and subcortical infarcts, and (3) <2 mm cortical microinfarcts and microhemorrhages. Multipathology was common and increased the risk of dementia significantly. Interpretation: These results indicate that AD-type neurodegenerative processes play the most prominent role in twilight cognitive decline. The high prevalence of both neurodegenerative and vascular pathologies indicates that multiple preventive and therapeutic approaches are needed to protect the brains of the oldest old.Peer reviewe

Primary age-related tauopathy in a Finnish population-based study of the oldest old (Vantaa 85+)

Abstract Aims Few studies have investigated primary age-related tauopathy (PART) in a population-based setting. Here, we assessed its prevalence, genetic background, comorbidities and features of cognitive decline in an unselected elderly population. Methods The population-based Vantaa 85+ study includes all 601 inhabitants of Vantaa aged ≥ 85 years in 1991. Neuropathological assessment was possible in 301. Dementia (DSM IIIR criteria) and Mini-Mental State Examination (MMSE) scores were assessed at the baseline of the study and follow-ups. PART subjects were identified according to the criteria by Crary et al and were compared with subjects with mild and severe Alzheimer's disease (AD) neuropathological changes. The effects of other neuropathologies were taken into account using multivariate and sensitivity assays. Genetic analyses included APOE genotypes and 29 polymorphisms of the MAPT 3′ untranslated region (3′UTR region). Results The frequency of PART was 20n = 61/301, definite PART 5. When PART subjects were compared with those with severe AD pathology, dementia was less common, its age at onset was higher and duration shorter. No such differences were seen when compared with those with milder AD pathology. However, both AD groups showed a steeper decline in MMSE scores in follow-ups compared with PART. APOE ε4 frequency was lower, and APOE ε2 frequency higher in the PART group compared with each AD group. The detected nominally significant associations between PART and two MAPT 3′UTR polymorphisms and haplotypes did not survive Bonferroni correction. Conclusions PART is common among very elderly. PART subjects differ from individuals with AD-type changes in the pattern of cognitive decline, associated genetic and neuropathological features.Peer reviewe

Prediction models for dementia and neuropathology in the oldest old : the Vantaa 85+cohort study

BackgroundWe developed multifactorial models for predicting incident dementia and brain pathology in the oldest old using the Vantaa 85+ cohort.MethodsWe included participants without dementia at baseline and at least 2 years of follow-up (N=245) for dementia prediction or with autopsy data (N=163) for pathology. A supervised machine learning method was used for model development, considering sociodemographic, cognitive, clinical, vascular, and lifestyle factors, as well as APOE genotype. Neuropathological assessments included -amyloid, neurofibrillary tangles and neuritic plaques, cerebral amyloid angiopathy (CAA), macro- and microscopic infarcts, -synuclein pathology, hippocampal sclerosis, and TDP-43.ResultsPrediction model performance was evaluated using AUC for 10x10-fold cross-validation. Overall AUCs were 0.73 for dementia, 0.64-0.68 for Alzheimer's disease (AD)- or amyloid-related pathologies, 0.72 for macroinfarcts, and 0.61 for microinfarcts. Predictors for dementia were different from those in previous reports of younger populations; for example, age, sex, and vascular and lifestyle factors were not predictive. Predictors for dementia versus pathology were also different, because cognition and education predicted dementia but not AD- or amyloid-related pathologies. APOE genotype was most consistently present across all models. APOE alleles had a different impact: epsilon 4 did not predict dementia, but it did predict all AD- or amyloid-related pathologies; epsilon 2 predicted dementia, but it was protective against amyloid and neuropathological AD; and epsilon 3 epsilon 3 was protective against dementia, neurofibrillary tangles, and CAA. Very few other factors were predictive of pathology.ConclusionsDifferences between predictors for dementia in younger old versus oldest old populations, as well as for dementia versus pathology, should be considered more carefully in future studies.Peer reviewe

Genetic and Epigenetic Characteristics of Inflammatory Bowel Disease–Associated Colorectal Cancer

doi: 10.1053/j.gastro.2021.04.042Background & Aims Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder associated with an elevated risk of colorectal cancer (CRC). IBD-associated CRC (IBD-CRC) may represent a distinct pathway of tumorigenesis compared to sporadic CRC (sCRC). Our aim was to comprehensively characterize IBD-associated tumorigenesis integrating multiple high-throughput approaches, and to compare the results with in-house data sets from sCRCs. Methods Whole-genome sequencing, single nucleotide polymorphism arrays, RNA sequencing, genome-wide methylation analysis, and immunohistochemistry were performed using fresh-frozen and formalin-fixed tissue samples of tumor and corresponding normal tissues from 31 patients with IBD-CRC. Results Transcriptome-based tumor subtyping revealed the complete absence of canonical epithelial tumor subtype associated with WNT signaling in IBD-CRCs, dominated instead by mesenchymal stroma-rich subtype. Negative WNT regulators AXIN2 and RNF43 were strongly down-regulated in IBD-CRCs and chromosomal gains at HNF4A, a negative regulator of WNT-induced epithelial–mesenchymal transition (EMT), were less frequent compared to sCRCs. Enrichment of hypomethylation at HNF4α binding sites was detected solely in sCRC genomes. PIGR and OSMR involved in mucosal immunity were dysregulated via epigenetic modifications in IBD-CRCs. Genome-wide analysis showed significant enrichment of noncoding mutations to 5′untranslated region of TP53 in IBD-CRCs. As reported previously, somatic mutations in APC and KRAS were less frequent in IBD-CRCs compared to sCRCs. Conclusions Distinct mechanisms of WNT pathway dysregulation skew IBD-CRCs toward mesenchymal tumor subtype, which may affect prognosis and treatment options. Increased OSMR signaling may favor the establishment of mesenchymal tumors in patients with IBD.BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder associated with an elevated risk of colorectal cancer (CRC). IBD-associated CRC (IBD-CRC) may represent a distinct pathway of tumorigenesis compared to sporadic CRC (sCRC). Our aim was to comprehensively characterize IBD-associated tumorigenesis integrating multiple high-throughput approaches, and to compare the results with in-house data sets from sCRCs. METHODS: Whole-genome sequencing, single nucleotide polymorphism arrays, RNA sequencing, genome-wide methylation analysis, and immunohistochemistry were performed using fresh-frozen and formalin-fixed tissue samples of tumor and corresponding normal tissues from 31 patients with IBD-CRC. RESULTS: Transcriptome-based tumor subtyping revealed the complete absence of canonical epithelial tumor subtype associated with WNT signaling in IBD-CRCs, dominated instead by mesenchymal stroma-rich subtype. Negative WNT regulators AXIN2 and RNF43 were strongly down-regulated in IBD-CRCs and chromosomal gains at HNF4A, a negative regulator of WNTinduced epithelial-mesenchymal transition (EMT), were less frequent compared to sCRCs. Enrichment of hypomethylation at HNF4 alpha binding sites was detected solely in sCRC genomes. PIGR and OSMR involved in mucosal immunity were dysregulated via epigenetic modifications in IBD-CRCs. Genome-wide analysis showed significant enrichment of noncoding mutations to 50 untranslated region of TP53 in IBD-CRCs. As reported previously, somatic mutations in APC and KRAS were less frequent in IBD-CRCs compared to sCRCs. CONCLUSIONS: Distinct mechanisms of WNT pathway dysregulation skew IBD-CRCs toward mesenchymal tumor subtype, which may affect prognosis and treatment options. Increased OSMR signaling may favor the establishment of mesenchymal tumors in patients with IBD.Peer reviewe

Tailoring of Optoelectronic Properties of ϵ-Fe2O3 Thin Films Through Insertion of Organic Interlayers

| openaire: EC/H2020/339478/EU//LAYERENG-HYBMATCombined atomic/molecular layer deposition (ALD/MLD) technique enables the engineering of inorganic–organic superlattices with atomic/molecular layer accuracy for the individual layer thicknesses. Here we demonstrate how the optical and electronic properties of ϵ-Fe2O3 thin films can be gradually tuned with an insertion of monomolecular organic layers. In our ϵ-Fe2O3:benzene superlattice (SL) structures the thickness of individual iron oxide layers varies in the range of 1–17 nm. With decreasing ϵ-Fe2O3 layer thickness, that is, SL period, the films become more transparent. Moreover revealed from the UV–vis spectra is that the indirect optical bandgap increases from ≈2.0 eV for ϵ-Fe2O3 up to ≈2.3 eV for the SL films with the shortest SL period. We foresee that the ALD/MLD approach presented here for the ϵ-Fe2O3–benzene thin films can be exploited in fabricating many other interesting hybrid material systems with controlled optoelectronic properties.Peer reviewe