CLU, CR1 and PICALM genes associate with Alzheimer's-related senile plaques

Introduction APOE is the strongest risk gene for sporadic Alzheimer's disease (AD) so far. Recent genome wide association studies found links for sporadic AD with CLU and CR1 involved in Aβ clearance, and PICALM affecting intracellular trafficking. Methods We investigated the associations of senile plaques (SP) and neurofibrillary tangles (NFT) with the proposed risk genes and APOE, in the Tampere Autopsy Study (TASTY) series (603 cases), a sample of the general population (0 to 97 yrs), who died out-of-hospital. Results Age and the APOEε4 allele associated strongly with all phenotypes of SP, as expected. In age and APOEε4 adjusted analyses, compared to the most common homozygous genotype, burnt out SP were more common among carriers of the C-allele of CLU, whereas the T-allele of PICALM and C-allele of CR1 were linked with lower SP coverage. We found no significant associations between any of the genetic variants and NFT. Conclusions Marginal effects from CLU, CR1 and PICALM suggest that these genes have minimal effects on the development of AD lesions.BioMed Central Open acces

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

Peer reviewe

A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson's disease

The dual-hit hypothesis of Parkinson's disease (PD) originally postulated that a neurotropic pathogen leads to formation of alpha-synuclein pathology in the olfactory bulb (OB) and dorsal motor nucleus of the vagus (DMV) and then invades the brain from these two entry points. Little work has been conducted to validate an important underlying premise for the dual-hit hypothesis, namely that the initial Lewy pathology does arise simultaneously in the OB and the enteric nervous system (ENS) plexuses and DMV at the earliest disease stage. We conducted a focused re-analysis of two postmortem datasets, which included large numbers of mild Lewy body disease (LBD) cases. We found that cases with alpha-synuclein pathology restricted to the peripheral autonomic nervous system and/or lower brainstem (early body-first LBD cases) very rarely had any OB pathology, suggesting that Lewy pathology commonly arises in the ENS without concomitant involvement of the OB. In contrast, cases with mild amygdala-predominant Lewy pathology (early brain-first LBD cases) nearly always showed OB pathology. This is compatible with the first pathology being triggered in the OB or amygdala followed by secondary spreading to connected structures, but without early involvement of the ENS or lower brainstem. These observations support that the pathologic process starts in either the olfactory bulb or the ENS, but rarely in the olfactory bulb and gut simultaneously. More studies on neuropathological datasets are warranted to reproduce these findings. The agreement between the revised single-hit hypothesis and the recently proposed brain-first vs. body-first model of LBD is discussed.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

Preventing obesity in infants: the growing healthy feasibility trial protocol

INTRODUCTION: Early childhood is an important period for establishing behaviours that will affect weight gain and health across the life course. Early feeding choices, including breast and/or formula, timing of introduction of solids, physical activity and electronic media use among infants and young children are considered likely determinants of childhood obesity. Parents play a primary role in shaping these behaviours through parental modelling, feeding styles, and the food and physical activity environments provided. Children from low socio-economic backgrounds have higher rates of obesity, making early intervention particularly important. However, such families are often more difficult to reach and may be less likely to participate in traditional programs that support healthy behaviours. Parents across all socio-demographic groups frequently access primary health care (PHC) services, including nurses in community health services and general medical practices, providing unparalleled opportunity for engagement to influence family behaviours. One emerging and promising area that might maximise engagement at a low cost is the provision of support for healthy parenting through electronic media such as the Internet or smart phones. The Growing healthy study explores the feasibility of delivering such support via primary health care services. METHODS: This paper describes the Growing healthy study, a non-randomised quasi experimental study examining the feasibility of an intervention delivered via a smartphone app (or website) for parents living in socioeconomically disadvantaged areas, for promoting infant feeding and parenting behaviours that promote healthy rather than excessive weight gain. Participants will be recruited via their primary health care practitioner and followed until their infant is 9 months old. Data will be collected via web-based questionnaires and the data collected inherently by the app itself. ETHICS AND DISSEMINATION: This study received approval from the University of Technology Sydney Ethics committee and will be disseminated via peer-reviewed publications and conference presentations

Changes in the metabolic profile of human male postmortem frontal cortex and cerebrospinal fluid samples associated with heavy alcohol use

Heavy alcohol use is one of the top causes of disease and death in the world. The brain is a key organ affected by heavy alcohol use. Here, our aim was to measure changes caused by heavy alcohol use in the human brain metabolic profile. We analyzed human postmortem frontal cortex and cerebrospinal fluid (CSF) samples from males with a history of heavy alcohol use (n = 74) and controls (n = 74) of the Tampere Sudden Death Series cohort. We used a nontargeted liquid chromatography mass spectrometry-based metabolomics method. We observed differences between the study groups in the metabolite levels of both frontal cortex and CSF samples, for example, in amino acids and derivatives, and acylcarnitines. There were more significant alterations in the metabolites of frontal cortex than in CSF. In the frontal cortex, significant alterations were seen in the levels of neurotransmitters (e.g., decreased levels of GABA and acetylcholine), acylcarnitines (e.g., increased levels of acylcarnitine 4:0), and in some metabolites associated with alcohol metabolizing enzymes (e.g., increased levels of 2-piperidone). Some of these changes were also significant in the CSF samples (e.g., elevated 2-piperidone levels). Overall, these results show the metabolites associated with neurotransmitters, energy metabolism and alcohol metabolism, were altered in human postmortem frontal cortex and CSF samples of persons with a history of heavy alcohol use

CRP gene variation affects early development of Alzheimer's disease-related plaques

Introduction We used the Tampere Autopsy Study (TASTY) series (n = 603, age 0-97 yrs), representing an unselected population outside institutions, to investigate the pathogenic involvement of inflammation in Alzheimer's disease-related lesions. Methods We studied senile plaque (SP), neurofibrillary tangles (NFT) and SP phenotype associations with 6 reported haplotype tagging single nucleotide polymorphisms (SNPs) in the CRP gene. CRP and Aβ immunohistochemistry was assessed using brain tissue microarrays. Results In multivariate analyses (age- and APOE-adjusted), non-neuritic SP were associated with the high-CRP TA-genotype (3.0% prevalence) of rs3091244 and CA-genotype (10.8%) of rs3093075 compared to common genotypes. Conversely, the low-CRP C allele (39.3%) of rs2794521 reduced the risk of harbouring early non-neuritic SP, compared to the TT genotype. CRP haplotype TAGCC (high) associated with non-neuritic SP, whereas haplotype CCGCC offered protection. TT genotypes (high) of rs3091244 and rs1130864 were associated with CRP staining. There were no associations between SNPs or haplotypes and NFT. CRP staining of the hippocampal CA1/2 region correlated with Aβ staining. Conclusions CRP gene variation affects early SP development in prodromal Alzheimer's disease, independent of APOE genotype.BioMed Central Open acces

Key lessons and impact of the growing healthy mHealth program on milk feeding, timing of introduction of solids, and infant growth: quasi-experimental study

BACKGROUND: The first year of life is an important window to initiate healthy infant feeding practices to promote healthy growth. Interventions delivered by mobile phone (mHealth) provide a novel approach for reaching parents; however, little is known about the effectiveness of mHealth for child obesity prevention. OBJECTIVE: The objective of this study was to determine the feasibility and effectiveness of an mHealth obesity prevention intervention in terms of reach, acceptability, and impact on key infant feeding outcomes. METHODS: A quasi-experimental study was conducted with an mHealth intervention group (Growing healthy) and a nonrandomized comparison group (Baby\u27s First Food). The intervention group received access to a free app and website containing information on infant feeding, sleep and settling, and general support for parents with infants aged 0 to 9 months. App-generated notifications directed parents to age-and feeding-specific content within the app. Both groups completed Web-based surveys when infants were less than 3 months old (T1), at 6 months of age (T2), and 9 months of age (T3). Survival analysis was used to examine the duration of any breastfeeding and formula introduction, and cox proportional hazard regression was performed to examine the hazard ratio for ceasing breast feeding between the two groups. Multivariate logistic regression with adjustment for a range of child and parental factors was used to compare the exclusive breastfeeding, formula feeding behaviors, and timing of solid introduction between the 2 groups. Mixed effect polynomial regression models were performed to examine the group differences in growth trajectory from birth to T3. RESULTS: A total of 909 parents initiated the enrollment process, and a final sample of 645 parents (Growing healthy=301, Baby\u27s First Food=344) met the eligibility criteria. Most mothers were Australian born and just under half had completed a university education. Retention of participants was high (80.3%, 518/645) in both groups. Most parents (226/260, 86.9%) downloaded and used the app; however, usage declined over time. There was a high level of satisfaction with the program, with 86.1% (143/166) reporting that they trusted the information in the app and 84.6% (170/201) claiming that they would recommend it to a friend. However, some technical problems were encountered with just over a quarter of parents reporting that the app failed to work at times. There were no significant differences between groups in any of the target behaviors. Growth trajectories also did not differ between the 2 groups. CONCLUSIONS: An mHealth intervention using a smartphone app to promote healthy infant feeding behaviors is a feasible and acceptable mode for delivering obesity prevention intervention to parents; however, app usage declined over time. Learnings from this study will be used to further enhance the program so as to improve its potential for changing infant feeding behaviors

Alzheimer´s disease neuropathology and inflammation: A genetic and immunohistochemical study

Alzheimerin taudin yleisyys ja yleistyminen ikääntyneessä väestössä kuormittaa jo nyt terveydenhuoltoa. Toistaiseksi ainoa kiistaton aikuisiässä ilmenevän Alzheimerin taudin riskitekijä on Apolipoproteiini E (APOE)-geenin ε4-alleeli. Myös eräiden muiden geenien yhteys sairastumisriskiin on löydetty mutta niiden vaikutus on ollut huomattavasti APOE-geeniä pienempi. Alzheimerin taudille tunnusomaisena on pidetty aivoissa tapahtuvia amyloidin kertymämuutoksia, jotka ilmenevät seniilien plakkien (SP) ja neurofibrillimuutosten eli tangeleiden (NFT) ilmaantumisena aivoihin. Tämän väitöskirjatyön tarkoituksena oli kartoittaa neuropatologisten muutosten esiintymistä oireettomalla väestöllä ja tarkastella Apolipoproteiini (APOE) geenin, C-reaktiivinen proteiini (CRP) geenin, Klusterin (CLU) geenin, CR1 (Complement component 3b/4b receptor 1) geenin, PICALM (Phosphatidylinositol binding clathrin assembly protein) geenin sekä USF1 (upstream stimulatory factor 1) geenin polymorfioiden vaikutusta Tampere Autopsy Study (TASTY)-tutkimusaineistossa. SP:t olivat selkeästi yleisempiä APOEε4alleelin kantajilla, erityisesti keski-iässä, ja hieman harvinaisempia APOEε2-alleelin kantajilla kuin niillä henkilöillä, joilla oli kaksi kopiota yleisimmästä ε3-geenimuodosta. Useat kohonneisiin CRP:n tasoihin liittyvät CRP-geenin yhden nukleotidin muutokset (single nucleotide polymorphisms, SNP) ja haplotyypit olivat yhteydessä kehityksessään alkuvaiheessa oleviin SP:hin. CRP- ja Aβ-proteiinien immunovärjäys osoitti näiden ekpressoituvan samoissa neuroneissa ja CRP-immunovärjäyksen intensiteetti korreloi CRP-geenin SNP:ien ja haplotyyppien kanssa. CLU-, CR1- ja PICALM SNP:ien ja SP:n välillä oli vain heikko yhteys verrattuna APOE:n vaikutukseen. USF1-geenin SNP:t ja haplotyypit olivat yhteydessä SP:hin ja NFT:hin Tampere Autopsy Study (TASTY)-tutkimusaineistossa. Tämän väitöskirjatyön tulosten perusteella tulehdusvastetta säätelevät geenit saattavat vaikuttaa Alzheimerin tautiin liittyvien aivojen kertymämuutosten kehittymiseen ja voivat siten olla yhteydessä myös sairauden syntyyn tai etenemiseen. On kuitenkin huomioitava, että ruumiinavausten yhteydessä koottu aineisto koostui enimmäkseen ei-dementoituneista henkilöistä. Kertymämuutosten yhteys kliinisen Alzheimerin taudin puhkeamiseen on siten kyseenalaista ja lisätutkimukset syy-seuraussuhteen selvittämiseksi ovat tarpeellisia.Alzheimer s disease (AD) affects a large proportion of the elderly population. To date, the only conclusive risk gene for sporadic AD is APOEε4. Many other genes and polymorphisms have been associated with AD, but the effects have been small. The pathogenic hallmarks found in postmortem AD brains are senile plaques (SP) and neurofibrillary tangles (NFT), formed from the accumulation of amyloid beta (Aβ) peptide and hyperphosphorylated tau (HP-tau) in neurons, although they also occur in undemented individuals. The objective of this thesis was to study the occurrence of these neuropathological lesions in tissue samples and their associations with polymorphisms of the genes of Apolipoprotein E (APOE), C-reactive protein (CRP), Clusterin (CLU), Complement component 3b/4b receptor 1 (CR1), Phosphatidylinositol binding clathrin assembly protein (PICALM) and Upstream transcription factor 1 (USF1) in the brains of a non-demented population (Tampere Autopsy Study TASTY; n=603). The APOEε4 allele strongly associated with the presence of SP in the TASTY series, most robustly in middle age, compared to the most common ε3/ε3 genotype. The ε2 allele appeared to show some form of protection, although not significant. A number of CRP single nucleotide polymorphisms (SNPs) and haplotypes related to elevated CRP protein levels were associated with early stage non-neuritic SP, with a trend in most cases for late stage neuritic SP. Both CRP immunohistochemistry (IHC) and Aβ peptide IHC staining correlated with each other, as did CRP IHC staining with CRP SNPs and haplotype pairs. Whilst CLU, CR1 and PICALM did associate with some variables of SP, they did so sparingly, and did not correlate with NFT. A number of USF1 SNPs and haplotypes associated with variables of SP and also with NFT in the TASTY series. Based on these results, it can be concluded that a number of inflammatory genes may influence the development of the neuropathological lesions associated with AD, and may therefore participate in the initiation or progression of the disease. Because these results were accumulated from an autopsy series consisting primarily of non-demented cases, there remains the question of the involvement of these AD-related lesions in disease aetiology. Further detailed studies investigating this much-discussed topic will be required and help to elucidate their contribution to Alzheimer s disease