New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Childhood sleep-disordered breathing – dentofacial and pharyngeal characteristics

Abstract The aim of this work was to examine distinct dentofacial and pharyngeal features in children with sleep-disordered breathing (SDB). A further aim was to test the validity of the conventional methods used in orthodontics for recognition of obstructed airways. Seventy children (36 girls, 34 boys, age range 4.2–11.9 years), who were diagnosed as having SDB during the years 2000–2002, constituted the source of subjects for four separate studies. The study protocol included otorhinolaryngological and orthodontic examinations. Dental impressions and lateral cephalograms were taken. In addition, upper airway was imaged in 36 children in different head postures by magnetic resonance imaging (MRI). Age- and gender-matched healthy children were used as controls. The results showed that children with SDB had increased overjet, smaller overbite, narrower upper and shorter lower dental arches and higher incidence of anterior open bite and distal molar relationship when compared with control children. The severity of the obstruction correlated with larger deviations from normal in the dental characteristics. There were more children with crowding and with anterior open bite with increased severity of the disorder. Children with SDB displayed an increased sagittal jaw relationship, a more vertical growth pattern of the mandible, a longer and thicker soft palate, a lower hyoid bone position, larger craniocervical angles and narrower pharyngeal airway measured at multiple levels, when compared with the controls. Deviation in pharyngeal variables showed highest correlation with the severity of SDB. MRI indicated a smaller than normal oropharyngeal airway in children with SDB. The effect of head posture on pharyngeal airway dimensions differed in children with SDB when compared with the controls. These findings verify that the developmental course of occlusal characteristics and craniofacial structures may be modulated by breathing pattern, and, on the other hand, that certain features may predispose to the development of the disorder. It is important to recognize these signs in order to guide further development in a more favorable direction. The results confirmed that cephalometry is a valid screening tool when assessing nasopharyngeal and retropalatal airway dimensions. Clinical examination of tonsillar size was found reliable when retroglossal airway size was evaluated.Tiivistelmä Väitöskirjatyön tarkoituksena oli selvittää lasten unenaikaisten hengityshäiriöiden yhteyttä kasvojen ja leukojen kasvuun, purennan kehitykseen sekä ylempien hengitysteiden rakenteeseen. Lisäksi tutkittiin, kuinka luotettavasti hammaslääkäreiden käytössä olevin menetelmin pystytään arvioimaan lasten ahtautuneita ilmateitä. Tutkimusaineistossa oli mukana 70 lasta (36 tyttöä, 30 poikaa, ikä 4.2–11.9 vuotta), joilla diagnosoitiin unenaikainen obstruktiivinen hengityshäiriö vuosina 2000–2002. Lapsille tehtiin kliiniset tutkimukset oikojahammaslääkärin ja korva-, nenä- ja kurkkutautien erikoislääkärin toimesta sekä otettiin lateraalikallokuva ja hampaistosta kipsimallijäljennökset. Lisäksi ylempien hengitysteiden magneettitutkimus suoritettiin 36 lapselle eri pään asennoissa. Verrokkiryhmässä oli sama ikä- ja sukupuolijakauma kuin tutkimusryhmässä. Tulokset osoittivat, että unenaikaisista hengityshäiriöistä kärsivillä lapsilla horisontaalinen ylipurenta oli suurentunut, vertikaalinen ylipurenta oli pienentynyt, ylähammaskaari oli kapeampi ja alahammaskaari lyhyempi kuin terveillä verrokeilla. Alaetualueen ahtaus ja etualueen avopurenta olivat yleisempiä niillä lapsilla, joilla oli vaikeampiasteinen hengityshäiriö. Lasten unenaikaiset hengityshäiriöt liittyivät suurentuneeseen leukojen väliseen kokoepäsuhtaan, alaleuan avautuvaan kasvumalliin, pidempään ja paksumpaan pehmeään suulakeen, kieliluun alempaan asentoon, kohonneeseen pään asentoon sekä ahtaampiin nielun ilmatilan mittoihin verrattaessa terveisiin lapsiin. Häiriön vaikeusaste korreloi suurempiin poikkeamiin nielun mitoissa. Lapsilla, joilla todettiin unenaikainen hengityshäiriö, magneettitutkimukset osoittivat nielun olevan ahdas. Pään asennon vaikutukset ilmatien rakenteeseen poikkesivat unenaikaisista hengityshäiriöistä kärsivillä lapsilla. Saadut tulokset osoittivat, että hengitystapa voi vaikuttaa hampaiston, kasvojen ja leukojen rakenteiden kehitykseen. Tietyt kasvojen ja leukojen piirteet puolestaan saattavat altistaa häiriön kehittymiselle. On tärkeää tunnistaa nämä merkit, jotta kehitystä voidaan ohjata suotuisampaan suuntaan. Tutkimukset osoittivat, että kefalometrinen analyysi on luotettava arvioitaessa nenänielun sekä pehmeän suulaen takana olevan ilmatilan kokoa. Nielurisojen kliinisen koon arviointi on luotettava arvioitaessa alemman suunielun ilmatilan kokoa

Airway and hard tissue dimensions in children treated with early and later timed cervical headgear:a randomized controlled trial

Abstract Background: A Kloehn-type cervical headgear (CH) aims to correct skeletal jaw discrepancy in Class II children. A few studies have reported CH treatment effects on airway dimensions, but none of them have been randomized according to timing. Objectives: To evaluate related craniofacial structures and pharyngeal airway dimensions in children with a Class II occlusion treated with CH and randomized into early and late treatment groups. Trial design: Randomized, parallel-group, prospective controlled trial. Methods: The material comprised 67 seven-year-old children with a Class II occlusion. Sealed-envelope randomization in 1:1 ratio was used to divide the children into two equal groups. In the early group (EG, n = 33), CH treatment was started immediately or after eruption of the first maxillary molars. In the second, late group (LG, n = 34), the active CH treatment was started about one and half year later. The active CH treatment was continued in both groups until normal Class I occlusion on first molars was achieved. Cephalometric radiographs were taken from both groups at the beginning of follow-up (T0), at the beginning of CH treatment of the second group (T1), and at the end of CH treatment of the second group (T2). Changes in cephalometric measurements were used as primary outcomes. Blinding was applicable for outcome assessment. Results: Fifty-six children completed the study. The posterior change in the position of the maxilla was significant for early treatment males at T0–T1 (SNA; P < 0.001, ANB; P = 0.009) and T0–T2 (SNA; P = 0.012). The palato-mandibular angle (PL-ML) decreased during T0–T1 in early treatment females (P = 0.018) and early treatment males (P = 0.037). The retroglossal airway increased (P = 0.010) in early treatment males at T0–T1. Highly significant positive correlations (P < 0.001) between skeletal and upper airway dimensions during early CH treatment were found in males. No harms were encountered. Conclusions: Despite the effective CH treatment, no harmful upper airway changes were found. Clinical registration: NCT02010346

Comparison of effects of cervical headgear treatment on skeletal facial changes when the treatment time is altered:a randomized controlled trial

Summary Background: There is a lack of evidence based on longitudinal information in the field of Class II malocclusion management with cervical headgear (CH), especially in a randomized setting. Objectives: The main objective of this study was to evaluate skeletal facial changes, particularly in vertical dimensions, after Kloehn-type CH treatment in children when the timing of treatment is altered. Trial design: Prospective, parallel-group, randomized controlled trial. Methods: Screened children with Class II malocclusion were randomized in 1:1 ratio to two groups of equal size by sealed-envelope randomization: the early group (EG), where active CH treatment was started at the age of 7.8 years, and the late group (LG), where CH treatment was started at the age of 9.5 years. The active treatment was continued until normal Class I occlusion on first molars was achieved. Cephalograms were taken at three different time points. Changes in cephalometric measurements were compared between groups and genders. Blinding was applicable for outcome evaluation. Results: Of 67 randomized children, 56 completed the study. Upper face height increased during the CH treatment phase, as the parameter N–ANS increased significantly during the active treatments of EG (P < 0.05) and LG (P < 0.05). Also, the parameter NSL–PL increased significantly during the treatment of EG (P < 0.01) and during the treatment of LG (P < 0.01). The Gonial angle decreased significantly in the early CH treatment group compared to the later treatment group (T₀–T₂: P < 0.01). CH improved the antero-posterior jaw relationship. No harms were encountered. Conclusions: Although the upper face height increased, the mandible showed anterior rotation after CH treatment. The Gonial angle was significantly decreased in the EG compared to the LG. There were gender-specific differences in both sagittal and vertical dimensions when examining interrelations in dimensional changes. The differences found between the early and later treatment groups were not clinically important when the cephalometric results are considered. Clinical registration: ClinicalTrials.gov (NCT02010346)

Effects of headgear timing on dental arch changes from 7 to 18 years of age:a follow-up study

Abstract Background: Dental arch effects after cervical headgear (CHG) treatment have been researched from several different perspectives. However, the long-term effects of CHG timing are still unknown. Objectives: To analyse the long-term effects of CHG timing on dental arches. Material and methods: A total of 67 children with Angle Class II malocclusion comprised the study group in this trial. The participants were randomized into two equal-sized groups. In the early group (EG, n = 33), treatment was started after the eruption of the first upper molars. In the later-timed group (LG, n = 34), treatment was started 18 months later compared with the early group. Long-term effects were measured from dental casts taken at five time points between 7 and 18 years of age. Results: The total maxillary dental arch length was achieved earlier, the gained length persisted better in the long term, and significantly more space was achieved in EG compared with LG (P = .048). The intermolar width in the maxillary dental arch was more stable and was reached earlier in EG compared with LG (P = .002). The results showed that in terms of total mandibular arch length increases, EG males benefited the most and LG females the least from CHG treatment (P = .031). Conclusions: Both genders benefited from earlier CHG treatment. The maxillary dental arches remained longer, and the final width was gained earlier in EG compared with LG

Dental arch effects after early and later timed cervical headgear treatment—a randomized controlled trial

Summary Background: Cervical headgear (CH) is a commonly used orthodontic appliance and its dentoalveolar changes are known. However, the effects related to gender and timing have gained less attention. Objectives: To examine dimensions of dental arches among children with Class II occlusion without posterior mandibular rotation according to timing of Kloehn-type CH treatment. Trial design: Prospective, randomized, parallel-group controlled trial. Methods: Sixty-seven seven-year-old children with a Class II occlusion were included in the study. The children were randomized into two equal-size groups in 1:1 ratio by sealed-envelope randomization. The early group (EG, n = 33) was treated between T₀ and T₁ (26 months), right after eruption of the first maxillary molars. The late group (LG, n = 34) was treated between T₁ and T₂ (24 months). The children were treated with CH until normal Class I occlusion on first molars was achieved. Impressions for dental casts were taken from all participants at T₀, T₁, and T₂. Blinding was applicable for outcome assessors. Changes in dental cast measurements were compared between the groups and genders using t-test, Mann-Whitney U-test, and repeated measures analysis of variance. Results: Of the children, 56 completed the study. The maxillary arch length and the transversal changes between the upper canines and upper first molars were significantly increased in EG at T₀−T₁ (P < 0.001). At T₂, the transversal dimension between the upper first molars was larger (P < 0.05), and in the lower arch the mandibular arch length (P < 0.05) and the transversal dimension between the lower first molars (P < 0.01) were increased in EG males compared to LG males. No harms were encountered. Conclusions: The male gender benefits most from early timing of the CH treatment, showing larger dimensions at the end of the follow-up. The results clearly indicated a wider and longer upper dental arch and spontaneous expansion of the lower dental arch after treatment. Clinical registration: NCT02010346