Aivojen vanhenemisen »geneettinen koodi»

Teema: Terveet aivot 100 vuotta. English summaryNon peer reviewe

Yleisten aivorappeumasairauksien laajeneva kirjo

Vertaisarvioitu.Viimeaikaiset neuropatologiset tutkimukset ovat osoittaneet yleisten aivorappeumasairauksien olevan oletettua heterogeenisempia. Alzheimerin taudista ja lewynkappaledementiasta on tunnistettu alatyyppejä, jotka eroavat klassisista muodoista tautimuutosten anatomisen jakauman ja kliinisen kuvan osalta. Lisäksi on tunnistettu uudentyyppisiä neuropatologisia entiteettejä, joiden kliininen kuva muistuttaa erityisesti Alzheimerin tautia. Limbinen TDP-43-enkefalopatia (LATE) on TDP-43-proteiinin kertymätauti. Primaarisessa ikätauopatiassa (PART) todetaan kohtalaisen runsasta hermosäietyyppistä tau-patologiaa, mutta ei juurikaan beeta-amyloidipatologiaa. Monet uudentyyppisistä tautimuodoista ovat varsin yleisiä erityisesti yli 80-vuotiaiden ikäryhmässä ja koskettavat väestön ikääntymisen myötä maailmanlaajuisesti miljoonia ihmisiä. Tautimuotojen kliinisten ja patologisten piirteiden tunnistaminen ja nykyistä paremmat diagnostiset työkalut ovat edellytys tautispesifisten hoitojen kehittämiselle.Peer reviewe

Causes of death of professional musicians in the classical genre

OBJECTIVE. Music practice and listening have been reported to have favorable effects on human health, but empirical data are largely missing about these effects. To obtain more information about the effect of exposure to music from early childhood, we examined the causes of death of professional musicians in the classical genre. METHODS: We used standardized mortality ratios (SMR) for Finnish performing artists (n=5,780) and church musicians (n=22,368) during 1981-2016. We examined deaths from cardiovascular diseases, cancers, and neurodegenerative and alcohol-related diseases. The diagnoses were based on the ICD-10, with data obtained from Statistics of Finland. RESULTS: Overall, SMR for all-cause mortality was 0.59 (95% CI 0.57-0.61) for church musicians and 0.75 (95% CI 0.70-0.80) for performing artists, suggesting a protective effect of music for health. In contrast, we found increased mortality in alcohol-related diseases among female performing artists (SMR 1.85, 95% CI 1.062.95) and in neurodegenerative diseases among male performing artists (1.46, 95% CI 1.13-1.84). Additionally, we found higher SMRs for female than male church musicians for cancers (SMRfemales 0.90, 95% CI 0.83-0.97; SMRmales 0.60, 95% CI 0.54-0.67) and cardiovascular diseases (SMRfemales 0.75, 95% CI 0.68-0.82; SMRmales 0.58, 95% CI 0.54-0.64). CONCLUSIONS: Our results show that the causes of death in performers differ from those in church musicians. Performing artists are not protected from neurodegenerative diseases or alcohol-related deaths. The findings call for further study on the life-long effects of music in musicians.Peer reviewe

Clinical features and spectrum of NOTCH3 variants in Finnish patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Objectives Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by pathogenic variants in the NOTCH3 gene. In Finland, the majority of CADASIL patients carry the pathogenic founder variant c.397C>T, (p.Arg133Cys), but the spectrum of other NOTCH3 variants has not been investigated previously. The aim of the study was to investigate the spectrum and prevalence of NOTCH3 variants Finnish CADASIL patients and to examine the clinical features associated with them. Materials and Methods The spectrum of NOTCH3 variants and the clinical features associated with them were retrospectively examined in 294 Finnish CADASIL patients tested during January 1996 to October 2021 in the Medical Genetics laboratory of Department of Genomics of Turku University Hospital, where practically all samples of patients with suspected CADASIL in Finland are investigated. Results The most common NOTCH3 variants in the study cohort were c.397C>T, (p.Arg133Cys) (68%) and c.3206A>G p.(Tyr1069Cys) (18%), but other less common NOTCH3 variants were detected in as many as 14% of the patients. Eight of the detected NOTCH3 variants were novel: c.520T>A,p.(Cys174Ser), c.836A>G,p.(Gln279Arg), c.1369T>G,p.(Cys457Gly), c.1338C>G,p.(Cys446Trp), c.1564T>G,p.(Cys522Gly), c.2848T>G,p.(Cys950Gly), c.6102dup,p.(Gly2035Argfs*60), and c.2410+6C>G. Other NOTCH3 variants than p.Arg133Cys and p.Tyr1069Cys were more often associated with more severe clinical features. Conclusion This study revealed the genetic and clinical spectrum of CADASIL in the Finnish population. Sequencing of the whole NOTCH3 gene performing a gene-panel or exome sequencing is recommended when suspecting CADASIL.Peer reviewe

COVID-19-infektion neurologiset ilmentymät

Vertaisarvioitu.COVID-19-infektion neurologisista ilmentymistä kertynyt tieto on tapausselostusten ja -sarjojen hallitsemaa. Yleisimmät neurologiset ilmentymät ovat olleet haju- ja makuaistin muutokset. Aivoverenkiertohäiriöt, enkefalopatia ja immuunivälitteiset keskushermoston sairaudet tulevat usein esiin COVID-19-infektion komplikaatioina, mutta toisaalta Guillain-Barrén oireyhtymän osalta yhteys tähän infektioon kumottiin laajemmassa epidemiologisessa kohorttitutkimuksessa. Myös enkefaliitin, epileptisten kohtauksien, ääreishermoston sairauksien ja lihassairauksien on kuvattu liittyvän tähän infektioon. Neuropatologisissa tutkimuksissa tärkeimmät löydökset ovat olleet hypoksis-iskeeminen vaurio, verenvuodot ja epäspesifiset tulehdusmuutokset. Vielä odotellaan varmuutta siitä, aiheutuvatko kudosmuutokset viruksen invaasiosta aivoihin vai onko kyse epäsuorista muutoksista. Mekanismi SARS-CoV2-viruksen pääsylle aivokudokseen näyttäisi olevan olemassa. COVID-19-infektion jälkeisestä pitkittyneestä neurologisesta oireilusta tarvitaan lisää tutkimustietoa.Peer reviewe

Chorea-acanthocytosis associated with two novel heterozygous mutations in the VPS13A gene

Non peer reviewe

Hippocampal Sclerosis in the Oldest Old : A Finnish Population-Based Study

Background: There are only few population-based studies that have systemically investigated the prevalence of hippocampal sclerosis (HS) in the very old. The frequency of unilateral versus bilateral HS has been rarely studied. Objective: We investigated the prevalence and laterality of HS and its association with other neurodegenerative and vascular pathologies in a population-based sample of very elderly. Furthermore, the concomitant presence of immunoreactivity for TDP-43, p62, and HPtau was studied. Methods: The population-based Vantaa 85(+) study includes all inhabitants of the city of Vantaa, who were > 85 years in 1991 (n = 601). Neuropathological assessment was possible in 302 subjects. Severity of neuronal loss of CA sectors and subiculum was determined bilaterally by HE-staining. Immunohistochemistry performed using antibodies for TDP-43, p62, and HPtau. Results: Neuronal loss and pathological changes in the hippocampus sector CA1 and subiculum were observed in 47 of the 302 individuals (16%), and 51% of these changes were bilateral. HS without comorbid neurodegenerative pathology was found in 1/47 subjects with HS (2%). Dementia (p <0.001) and TDP-43 immunopositivity of the granular cell layer of the dentate fascia (p <0.001) were strongly associated with HS. The CERAD score, immunopositivity for HPtau and p62 in the granular cell layer of the fascia dentate were also associated. Conclusion: HS is prevalent (16%) in the oldest old population, but HS without any comorbid neurodegenerative pathology is rare. The high frequency of unilateral HS (49%) implied that bilateral sampling of hippocampi should be routine practice in neuropathological examination.Peer reviewe

Nuoren aikuisen etenevä neurokognitiivinen oireisto - muista perinnölliset syyt

Vertaisarvioitu.Kuvaamme vaikeaan etenevään neuropsykiatriseen oireistoon nuorena sairastuneen naisen, jonka sairaus johti menehtymiseen alle kahdessa vuodessa. Sairaus alkoi selkeillä psykiatrisilla oireilla, potilas oli vauhdikas, rajaton ja lopulta avoimen psykoottinen. Pian tämän jälkeen kehittyi kognitiivisia oireita kuten kielellisten ja päättelytoimintojen vaikeutta. Monipuolisten tutkimusten jälkeen sairaus paljastui otsa-ohimolohkorappeumaksi, jonka taustalla oli C9orf72-toistojaksomutaatio. Kyseessä oli nuorin tieteellisessä kirjallisuudessa dokumentoitu potilas, jolla oli tämän mutaation aiheuttama otsa-ohimolohkorappeuma

Genetic analysis reveals novel variants for vascular cognitive impairment

Objectives The genetic background of vascular cognitive impairment (VCI) is poorly understood compared to other dementia disorders. The aim of the study was to investigate the genetic background of VCI in a well-characterized Finnish cohort. Materials & Methods Whole-exome sequencing (WES) was applied in 45 Finnish VCI patients. Copy-number variant (CNV) analysis using a SNP array was performed in 80 VCI patients. This study also examined the prevalence of variants at the miR-29 binding site of COL4A1 in 73 Finnish VCI patients. Results In 40% (18/45) of the cases, WES detected possibly causative variants in genes associated with cerebral small vessel disease (CSVD) or other neurological or stroke-related disorders. These variants included HTRA1:c.847G>A p.(Gly283Arg), TREX1:c.1079A>G, p.(Tyr360Cys), COLGALT1:c.1411C>T, p.(Arg471Trp), PRNP: c.713C>T, p.(Pro238Leu), and MTHFR:c.1061G>C, p.(Gly354Ala). Additionally, screening of variants in the 3 ' UTR of COL4A1 gene in a sub-cohort of 73 VCI patients identified a novel variant c.*36T>A. CNV analysis showed that pathogenic CNVs are uncommon in VCI. Conclusions These data support pathogenic roles of variants in HTRA1, TREX1 and in the 3 ' UTR of COL4A1 in CSVD and VCI, and suggest that vascular pathogenic mechanisms are linked to neurodegeneration, expanding the understanding of the genetic background of VCI.Peer reviewe

Clinical features and spectrum of NOTCH3 variants in Finnish patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by pathogenic variants in the NOTCH3 gene. In Finland, the majority of CADASIL patients carry the pathogenic founder variant c.397C>T, (p.Arg133Cys), but the spectrum of other NOTCH3 variants has not been investigated previously. The aim of the study was to investigate the spectrum and prevalence of NOTCH3 variants Finnish CADASIL patients and to examine the clinical features associated with them.Materials and methods: The spectrum of NOTCH3 variants and the clinical features associated with them were retrospectively examined in 294 Finnish CADASIL patients tested during January 1996 to October 2021 in the Medical Genetics laboratory of Department of Genomics of Turku University Hospital, where practically all samples of patients with suspected CADASIL in Finland are investigated.Results: The most common NOTCH3 variants in the study cohort were c.397C>T, (p.Arg133Cys) (68%) and c.3206A>G p.(Tyr1069Cys) (18%), but other less common NOTCH3 variants were detected in as many as 14% of the patients. Eight of the detected NOTCH3 variants were novel: c.520T>A,p.(Cys174Ser), c.836A>G,p.(Gln279Arg), c.1369T>G,p.(Cys457Gly), c.1338C>G,p.(Cys446Trp), c.1564T>G,p.(Cys522Gly), c.2848T>G,p.(Cys950Gly), c.6102dup,p.(Gly2035Argfs*60), and c.2410+6C>G. Other NOTCH3 variants than p.Arg133Cys and p.Tyr1069Cys were more often associated with more severe clinical features.Conclusion: This study revealed the genetic and clinical spectrum of CADASIL in the Finnish population. Sequencing of the whole NOTCH3 gene performing a gene-panel or exome sequencing is recommended when suspecting CADASIL.</p