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

Alpha-synuclein pathology of olfactory bulbs/peduncles in the Vantaa85+cohort exhibit two divergent patterns : a population-based study

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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

Distribution of Lewy-related pathology in the brain, spinal cord, and periphery : the population-based Vantaa 85+study

Evolving evidence has supported the existence of two anatomically distinct Lewy-related pathology (LRP) types. Investigation of spinal cord and peripheral LRP can elucidate mechanisms of Lewy body disorders and origins of synuclein accumulation. Still, very few unselected studies have focused on LRP in these regions. Here we analysed LRP in spinal cord, dorsal root ganglion, and adrenal gland in the population-based Vantaa 85 + study, including every ≥ 85 years old citizen living in the city of Vantaa in 1991 (n = 601). Samples from spinal cord (C6-7, TH3-4, L3-4, S1-2) were available from 303, lumbar dorsal root ganglion from 219, and adrenal gland from 164 subjects. Semiquantitative scores of LRP were determined from immunohistochemically stained sections (anti-alpha-synuclein antibody 5G4). LRP in the ventral and dorsal horns of spinal cord, thoracic intermediolateral column, dorsal root ganglion and adrenal gland were compared with brain LRP, previously determined according to DLB Consortium criteria and by caudo-rostral versus amygdala-based LRP classification. Spinal LRP was found in 28% of the total population and in 61% of those who had LRP in the brain. Spinal cord LRP was found only in those subjects with LRP in the brain, and the quantity of spinal cord LRP was associated with the severity of brain LRP (p Peer reviewe

Putative risk alleles for LATE-NC with hippocampal sclerosis in population-representative autopsy cohorts

Limbic-predominant age-related TAR-DNA-binding protein-43 (TDP-43) encephalopathy with hippocampal sclerosis pathology (LATE-NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP-43-pathology, leading to cognitive dysfunction and dementia. Polymorphisms in GRN, TMEM106B and ABCC9 are proposed as LATE-NC + HS risk factors in brain bank collections. To replicate these results in independent population-representative cohorts, hippocampal sections from brains donated to three such studies (Cambridge City over 75-Cohort [CC75C], Cognitive Function and Ageing Study [CFAS], and Vantaa 85+ Study) were stained with hematoxylin-eosin (n = 744) and anti-pTDP-43 (n = 713), and evaluated for LATE-NC + HS and TDP-43 pathology. Single nucleotide polymorphism genotypes in GRN rs5848, TMEM106B rs1990622 and ABCC9 rs704178 were determined. LATE-NC + HS (n = 58) was significantly associated with the GRN rs5848 genotype (chi(2)(2) = 20.61, P <0.001) and T-allele (chi(2)(1) = 21.04, P <0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P <0.001) and A-allele (chi(2)(1) = 25.75, P <0.001). No differences in ABCC9 rs704178 genotype or allele frequency were found between LATE-NC + HS and non-LATE-NC + HS neuropathology cases. Dentate gyrus TDP-43 pathology associated with GRN and TMEM106B variations, but the association with TMEM106B nullified when LATE-NC + HS cases were excluded. Our results indicate that GRN and TMEM106B are associated with severe loss of CA1 neurons in the aging brain, while ABCC9 was not confirmed as a genetic risk factor for LATE-NC + HS. The association between TMEM106B and LATE-NC + HS may be independent of dentate TDP-43 pathology.Peer reviewe

APOE epsilon 4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue : a Finnish biobank, autopsy and clinical study

Apolipoprotein E epsilon 4 allele (APOE4) has been shown to associate with increased susceptibility to SARS-CoV-2 infection and COVID-19 mortality in some previous genetic studies, but information on the role of APOE4 on the underlying pathology and parallel clinical manifestations is scarce. Here we studied the genetic association between APOE and COVID-19 in Finnish biobank, autopsy and prospective clinical cohort datasets. In line with previous work, our data on 2611 cases showed that APOE4 carriership associates with severe COVID-19 in intensive care patients compared with non-infected population controls after matching for age, sex and cardiovascular disease status. Histopathological examination of brain autopsy material of 21 COVID-19 cases provided evidence that perivascular microhaemorrhages are more prevalent in APOE4 carriers. Finally, our analysis of post-COVID fatigue in a prospective clinical cohort of 156 subjects revealed that APOE4 carriership independently associates with higher mental fatigue compared to non-carriers at six months after initial illness. In conclusion, the present data on Finns suggests that APOE4 is a risk factor for severe COVID-19 and post-COVID mental fatigue and provides the first indication that some of this effect could be mediated via increased cerebrovascular damage. Further studies in larger cohorts and animal models are warranted.Peer reviewe

Diffusion tensor imaging is associated with motor outcomes of very preterm born children at 11 years of age

Aim Very preterm children born Methods A cohort of 37 very preterm infants (mean gestational age 29 4/7, SD 2 0/7) born in 2004-2006 in Turku University Hospital underwent diffusion tensor imaging at term. A region of interest analysis of fractional anisotropy and mean diffusivity was performed. Motor outcomes at 11 years of age were measured with the Movement Assessment Battery for Children - Second Edition. Results The diffusion metrics of the corpus callosum (genu P = .005, splenium P = .049), the left corona radiata (P = .035) and the right optic radiation (P = .017) were related to later motor performance. Mean diffusivity decreased and fractional anisotropy increased in proportion to the improving performance. Conclusion The diffusion metrics of the genu and splenium of the corpus callosum, the left corona radiata and the right optic radiation at term were associated with motor skills at 11 years of age. Diffusion tensor imaging should be further studied as a potential tool in recognising children at risk for motor impairment.</div

The somatic growth of a regional birth cohort of 351 preterm infants during the first two years of life

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HKPro3 - Valtion tukemien homekorjaushankkeiden arviointi: Jatkotutkimus

Valtioneuvoston vuoden 2013 kolmannen lisätalousarvion määrärahasta tuettujen sisäilma- ja kosteusvauriohankkeiden valtionavustusten myöntämisestä, maksamisesta ja käytöstä säädettiin Valtioneuvoston asetuksilla 875/2013 ja 1099/2013. Ehdoilla ja niitä koskevilla ohjeilla pyrittiin varmentamaan hankkeen toteutuksen laatu siten, että korjauksilla tai niitä korvaavalla uudisrakentamisella saadaan poistettua kaikki kohteen sisäilmaongelmat ja estettyä niiden uusiutuminen. Keskeisimmät vaatimukset ja uudistukset valtionavustusmenettelyyn olivat:a) Hakemukseen liitetty rakennusterveysasiantuntijan tai muun vastaavan pätevyyden omaavan asiantuntijan lausunto rakennuksen kunnosta ja tehdyistä tutkimuksista sekä sisäilmaongelman tai kosteusvaurion merkityksestä rakennuksen käyttäjille.b) Aloitusilmoitukseen liitetty ulkopuolisen asiantuntijan lausunto korjaussuunnitelmista ja lausunnonantajan vakuutus puolueettomuudestaan ja riippumattomuudestaan.Vaaditut lausunnot pohjautuvat vuoden 2012 lisätalousarvion valtionavustuksia jaettaessa kokeiltuun asiantuntijamenettelyyn, jossa ennalta nimetty arviointiryhmä kävi läpi kaikki avustushakemuksen jättäneet hankkeet. Vuoden 2013 lisämäärärahaa koskeneessa avustusmenettelyssä hakijoiden tuli itse hankkia asiantuntijalausunnot, joilla ei kuitenkaan havaittu samanlaista vaikuttavuutta kuin vuoden 2012 menettelyllä, koska lausuntojen laatu vaihteli erittäin paljon. Toisaalta kunnat olivat oppineet parempaa projektinhallintaa jo vuoden 2012 menettelyssä ja vuoden 2013 lisätalousarviosta jaettuihin, mutta vuoteen 2014 sijoittunut valtionavustusmenettely tuki samaa kehityskäyrää kuntien teknisten virastojen kosteusvauriokorjaamiseen liittyvän osaamisen kehittämisessä. Kehitystä ovat tukeneet myös muut hankkeet, mutta yhä edelleen kehitystä tulee tukea paitsi rakentamisprojektin hallintaan liittyvillä toimintamalleilla, myös kunnalliseen päätöksentekoon, hankkeiden priorisointiin ja rakennusten ylläpitoon liittyvissä asioissa sekä korjausten todelliseen onnistumiseen ja jälkiseuranta-asiakirjoihin paneutuvassa jatkotutkimuksessa.Avustusmenettely niin ikään kaipaa kehittämistä ja systematisointia. Tämä tutkimus painottui asiakirjojen laadun analysointiin, mutta erityisesti avustusmenettelyä tutkittiin kyselytutkimuksella. Tässä tutkimuksessa analysoitiin avustushakemusten käsittelyä ja sen yhdenmukaisuutta eri aluehallintovirastojen välillä. Hankkeiden käsittely poikkesi selvästi vuoden 2012 menettelystä, mutta tulokset olivat hyvin samankaltaisia. Molemmissa prosesseissa noin puolet hankkeista arvioitiin selvästi puutteelliseksi ehtoihin verrattuna. Vuoden 2013 lisämäärärahaan liittyi tiukemmat ehdot, mutta kaikille ehdot täyttäville myönnettiin valtionavustus. Molemmat avustusmenettelyt koettiin liian työläiksi ja aikatauluiltaan epäonnistuneiksi. Tutkimuksen tuloksena tutkimusryhmä luonnosteli lausuntolomakkeen, jota voidaan hyödyntää hankeosapuolien väliseen vuorovaikutukseen kaikissa homekorjaushankkeissa, mutta myös valtionavustusmenettelyssä varmentamaan, että kuntotutkimukset, hankesuunnitelma ja korjaussuunnitelmat ovat tekniseltä sisällöltään riittävät, toimivat ja laadukkaat. Tutkimuksen ohessa toteutettiin Satu Heinon diplomityö, joka julkaistaan vuoden 2016 alussa. Diplomityöstä otettiin laadunvarmistusta ja korjaussuunnitelmia koskevia osioita mukaan tähän loppuraporttiin