APOE ε4, Alzheimer's disease neuropathology, and sleep disturbance, in individuals with and without dementia

BACKGROUND: Apolipoprotein E epsilon 4 (APOE-ε4) carrier status is an established risk factor for Alzheimer’s disease (AD) dementia. It has also been linked with sleep disturbance in healthy older adults and increased insomnia risk. This association may be driven by the effect of APOE-ε4 on AD pathological change, itself associated with sleep abnormalities. To assess this relationship, we have evaluated post-mortem neuropathological findings in patients with and without cognitive impairment and AD pathology, who had extensive clinical assessment within 12 months of death. METHODS: This retrospective cohort study used UK Brain Banks Network data. Eligible subjects were aged over 50, with pre-mortem neuropsychiatry inventory scores of sleep disturbance (NPI-K), neurocognitive testing and functional cognitive status assessment (Clinical Dementia Rating scale). Neuropathological data included Thal phase, Braak stage and CERAD scores (measures of Aβ plaque distribution, tangle distribution and neuritic plaque density, respectively) combined to form the National Institute on Aging Alzheimer’s Association (NIA-AA) ABC score reflecting AD neuropathology. Participants with other significant intracerebral pathology or pathological features of non-AD dementia were excluded. Multivariate linear regression was performed with NPIK Global Score (NPIK frequency score multiplied by severity score) as the dependent variable and APOE-ε4 heterozygosity or homozygosity as independent variables. Covariates included age, gender, APOE-ε2 status and ABC NPI measures reflecting depression and anxiety. Further models stratified by ABC score and functional cognitive status were also produced. RESULTS: Seven hundred twenty-eight records were identified. Two hundred two participants were included in the final analysis: mean (SD) age 84.0 (9.2) and MMSE 14.0 (11.8). Mean sleep disturbance scores were highest in ε4 homozygosity (n=11), 4.55 (5.4); intermediate in ε4 heterozygosity (n=95), 2.03 (4.0); and lowest in non-ε4 carriers (n=96), 1.36 (3.3). Within the full sample, controlling for pathological status, age, gender, depression, anxiety and CDR-SOB status, APOE-ε4 homozygosity was associated with sleep disturbance (β 2.53, p=0.034). APOE-ε4 heterozygosity was similarly associated in individuals without dementia (β 1.21, p=0.048). CONCLUSION: These findings lend weight to the hypothesis that APOE-ε4 affects sleep by mechanisms independent of AD pathological change. Evaluation of those mechanisms would enhance understanding of sleep disturbance pathways and potentially provide treatment targets. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-022-00992-y

Kamo ide hrvatsko maloljetničko kazneno zakonodavstvo? - 1. dio

U radu se obrađuje kazneni postupak prema maloljetnicima pred sudom za mladež u svjetlu predstojećih izmjena Zakona o sudovima za mladež. Autor, najprije, ukazuje na bitne značajke hrvatskog kaznenog postupka prema maloljetnicima, te analizira kako su u postojeće maloljetničko zakonodavstvo ugrađena temeljna procesna prava maloljetnika iz odgovarajućih međunarodnih dokumenata (tzv. Pekinška pravila, Konvencija o pravima djeteta). Usporedni pregled organizacije i nadležnosti sudova za maloljetnike u 12 europskih zemalja pokazuje da u Europi dominiraju dva modela maloljetničkog pravosuđa: sudski i zaštitni model. S obzirom na dominantnu ulogu suca za mladež tijekom čitavog kaznenog postupka prema maloljetnicima, hrvatski sud za mladež može se ubrojiti u welfare model po kojemu sudac za mladež vrši ne samo istražnu funkciju u pripremnom postupku, nego i sudsku funkciju u postupku pred vijećem za mladež. Nakon prikaza i analize odluke Europskog suda za ljudska prava u predmetu Nortier v. The Netherlands koja se može primijeniti i na naše maloljetničko pravosuđe, te prikaza rezultata ankete provedene među sucima za mladež u Hrvatskoj, autor dolazi do zaključka da objedinjenje istražne i sudske funkcije kod suca za mladež ne predstavlja kršenje prava maloljetnika na nepristran sud iz čl. 6. st. 1. Konvencije za zaštitu ljudskih prava i temeljnih sloboda. Na kraju rada autor ukazuje na eventualne posljedice do kojih bi moglo doći uslijed dosljednog odvajanja istražne i sudske funkcije u postupku pred sudom za mladež