ASIC-E4: Interplay of Beta-Amyloid, Synaptic Density and Neuroinflammation in Cognitively Normal Volunteers With Three Levels of Genetic Risk for Late-Onset Alzheimer's Disease – Study Protocol and Baseline Characteristics

Background: Detailed characterization of early pathophysiological changes in preclinical Alzheimer's disease (AD) is necessary to enable development of correctly targeted and timed disease-modifying treatments. ASIC-E4 study (“Beta-Amyloid, Synaptic loss, Inflammation and Cognition in healthy APOE ε4 carriers”) combines state-of-the-art neuroimaging and fluid-based biomarker measurements to study the early interplay of three key pathological features of AD, i.e., beta-amyloid (Aβ) deposition, neuroinflammation and synaptic dysfunction and loss in cognitively normal volunteers with three different levels of genetic (APOE-related) risk for late-onset AD. Objective: Here, our objective is to describe the study design, used protocols and baseline demographics of the ASIC-E4 study. Methods/Design: ASIC-E4 is a prospective observational multimodal imaging study performed in Turku PET Centre in collaboration with University of Gothenburg. Cognitively normal 60–75-year-old-individuals with known APOE ε4/ε4 genotype were recruited via local Auria Biobank (Turku, Finland). Recruitment of the project has been completed in July 2020 and 63 individuals were enrolled to three study groups (Group 1: APOE ε4/ε4, N = 19; Group 2: APOE ε4/ε3, N = 22; Group 3: APOE ε3/ε3, N = 22). At baseline, all participants will undergo positron emission tomography imaging with tracers targeted against Aβ deposition (11C-PIB), activated glia (11C-PK11195) and synaptic vesicle glycoprotein 2A (11C-UCB-J), two brain magnetic resonance imaging scans, and extensive cognitive testing. In addition, blood samples are collected for various laboratory measurements and blood biomarker analysis and cerebrospinal fluid samples are collected from a subset of participants based on additional voluntary informed consent. To evaluate the predictive value of the early neuroimaging findings, neuropsychological evaluation and blood biomarker measurements will be repeated after a 4-year follow-up period. Discussion: Results of the ASIC-E4 project will bridge the gap related to limited knowledge of the synaptic and inflammatory changes and their association with each other and Aβ in “at-risk” individuals. Thorough in vivo characterization of the biomarker profiles in this population will produce valuable information for diagnostic purposes and future drug development, where the field has already started to look beyond Aβ

Improving lung cancer care using real-world data

Abstract Lung cancer remains the leading cause of cancer incidence and mortality worldwide although the treatment of lung cancer has improved significantly over recent decades. Challenges to improve lung cancer survival still remain. One aspect is the early diagnostics of lung cancer by screening or detecting early-stage lung cancers rather than advanced stage, as the five-year survival rate is 40–80% for stage I lung cancer and only 2–6% for stage IV. Another aspect is the improvement of the treatments; major improvements have been made especially in NSCLC treatment with the advent of targeted therapies, like EGFR TKIs, and immunotherapies. In this thesis, we wanted to investigate the association between lung cancer diagnostic delays and survival in a single Finnish cancer centre. In recent years, many centres have introduced fast-track diagnostic and treatment procedures for lung cancer, but it is uncertain whether they improve survival. In our study, shorter time intervals were not associated with improved survival, suggesting that fast-track approaches are unlikely to improve the survival of lung cancer patients. EGFR TKIs have significantly improved progression-free survival of NSCLC patients with sensitizing EGFR mutations. However, TKIs are associated with significant and disabling side effects, like rash and diarrhoea, which adversely affect quality of life and treatment compliance. In turn, it has been shown that patients who develop skin rash are more likely to respond to treatment. Rash can be relieved with tetracycline antibiotics and topical corticosteroids. Prophylactic use of tetracyclines has been shown to inhibit the severity of TKI rash, but it is unknown whether prophylactic use of tetracyclines and topical corticosteroids can increase the survival of NSCLC patients treated with EGFR TKIs. In this study, we present the results of a large nationwide cohort of patients treated with EGFR TKIs for NSCLC indication, using wide real-world registries. We found that prophylactic use of tetracyclines and topical corticosteroids can improve the survival of NSCLC patients treated with EGFR TKIs with high incidence of rash.Tiivistelmä Keuhkosyövän hoidossa on otettu suuria edistysaskelia viime vuosikymmenten aikana. Siitä huolimatta keuhkosyöpä on edelleen useimmin diagnosoitu syöpä ja suurin syöpäkuolleisuuden aiheuttaja maailmassa. Haasteita keuhkosyövän ennusteen parantamisessa riittää edelleen. Yksi näkökulma on varhaisen diagnostiikan parantaminen keuhkosyöpää seulomalla ja löytämällä enemmän varhaisen vaiheen keuhkosyöpiä. Asteen I keuhkosyövän 5-vuotiselossaolo on 40–80 %, kun taas asteen IV keuhkosyövissä se on vain 2–6 %. Toinen näkökulma on hoitojen kehittyminen: merkittävää hyötyä on nähty erityisesti ei-pienisoluisen keuhkosyövän hoidossa täsmähoitojen, kuten EGFR-estäjien, sekä immunologisten hoitojen kehityksen myötä. Tässä tutkimuksessa halusimme selvittää keuhkosyövän diagnostiikan viiveiden yhteyttä ennusteeseen suomalaisen syöpäkeskuksen potilailla. Monet syöpäkeskukset ovat kehittäneet nopean diagnostiikan ja hoidon polkuja keuhkosyöpäpotilaille, mutta on epävarmaa, voivatko ne parantaa ennustetta. Tässä tutkimuksessa nopea diagnostiikka tai hoidon aloitus ei parantanut ennustetta, joten nopeiden hoitopolkujen kehittäminen ei välttämättä tuo lisähyötyä keuhkosyöpäpotilaiden ennusteeseen. EGFR-estäjät ovat merkittävästi parantaneet ei-pienisoluisen EGFR-mutatoituneen keuhkosyövän tautivapaata-aikaa, mutta niihin liittyy huomattavia elämänlaatua ja hoitomyöntyvyyttä heikentäviä haittoja, kuten ihottumaa ja ripulia. Ihottuman esiintymisen on toisaalta osoitettu korreloivan hoidon tehon kanssa. Ihottumaa voidaan hoitaa tetrasykliiniryhmän antibiooteilla ja kortisonivoiteilla. Tetrasykliinien ennakoiva käyttö vähentää vakavan ihottuman riskiä, mutta on ollut epävarmaa, voiko näiden hoitojen ennakoiva käyttö parantaa potilaiden ennustetta. Tässä laajassa, kansallisessa tosielämän tietoja hyödyntävässä kohorttiaineistossa havaitsimme tetrasykliinien ja kortisonivoiteiden ennakoivan käytön parantavan ennustetta ei-pienisoluista keuhkosyöpää sairastavilla potilailla, jotka käyttävät suuren ihottumariskin EGFR-estäjiä

Geology and crystallization conditions of the Särkiniemi intrusion and related nickel-copper ore, central Finland:implications for depth of emplacement of 1.88 Ga nickel-bearing intrusions

Abstract Several Ni-Cu deposits occur within the Kotalahti area, central Finland, in proximity to an Archaean gneiss dome surrounded by a Palaeoproterozoic craton-margin supracrustal sequence comprising quartzites, limestones, calc-silicate rocks, black schists and banded diopside amphibolites. The geology of the area and age of the Ni-bearing intrusions (1.88 Ga) are similar to the Thompson Ni belt in the Canadian Trans-Hudson Orogen. The small mafic-ultramafic and Ni-Cu -bearing Särkiniemi intrusion, closely associated with the Archaean basement core of the Kotalahti Dome, is composed of a western peridotite and eastern gabbro body, both of which are mineralized. The eastern gabbro has a contact aureole several meters thick, consisting of orthopyroxene +/- cordierite bearing hornfels between the intrusion and the migmatites. Geochemically, the Särkiniemi intrusion shares many features in common with other Svecofennian mafic-ultramafic intrusions, including crustal contamination and nickel depletion. The related Ni-Cu deposit has a low Ni/Co value (15) and low nickel content in the sulphide fraction (2.8 wt.%), together with a low estimated magma/sulphide ratio of around 170. Svecofennian 1.88 Ga mafic-ultramafic intrusions occur in terrains of variable metamorphic grade (from low-amphibolite to granulite facies) and are likely to represent emplacement at different crustal depths. Multi-equilibrium thermobarometry indicates that the contact aureole at Särkiniemi reached equilibrium at pressures of 4.5–6 kbar (15–20 km depth) and temperatures of 600–670 °C. Combined with the results of earlier research on the Svecofennian intrusions, this study indicates that a depth of 15–20 km crustal level was favourable, along with other critical factors, for nickel sulfide deposition at 1.88 Ga

Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation

Background and Purpose-CADASIL is an autosomal dominant arteriopathy, characterized by multiple brain infarcts, cognitive decline, and finally dementia, which is caused by mutations in Notch3 gene encoding a Notch3 receptor protein. We describe the clinical, neuropsychological, imaging, genetic, and skin biopsy findings in a CADASIL patient homozygous for the C475T mutation resulting in R133C amino acid substitution, in comparison to 9 age-matched heterozygous patients with the same mutation. Methods-The patients were examined clinically and neuropsychologically and with MRI and positron emission tomography for assessment of cerebral blood flow. The gene defect was analyzed by sequencing the products of polymerase chain reaction of exons 3 and 4 of the Notch3 gene. Dermal arteries were analyzed electron microscopically. Results-The homozygous patient had his first-ever stroke at age 28 years. This is markedly earlier than the average, but the patient's heterozygous son had his first transient ischemic attack-like episode at the same age and another heterozygous patient had his first-ever stroke when only 2 years older. He was neuropsychologically more severely deteriorated than all but 1 of the heterozygous patients. These 2 patients had the most severe (confluent grade D) white matter MRI changes. Positron emission tomography showed markedly reduced cerebral blood flow. Skin biopsy revealed profuse deposits of granular osmiophilic material. The progression of disease in the homozygous case was, however, slower than in the most severely affected heterozygous patient. Conclusions-Our homozygous patient's phenotype is within the clinical spectrum of CADASIL, although at its severe end. Thus, CADASIL may follow the classic definition of a dominant disease, according to which the heterozygous and homozygous patients are clinically indistinguishable.Peer reviewe