Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment.

INTRODUCTION: Plasma glial fibrillary acidic protein (GFAP) is a marker of astroglial activation and astrocytosis. We assessed the ability of plasma GFAP to detect Alzheimer's disease (AD) pathology in the form of AD-related amyloid-β (Aβ) pathology and conversion to AD dementia in a mild cognitive impairment (MCI) cohort. METHOD: One hundred sixty MCI patients were followed for 4.7 years (average). AD pathology was defined using cerebrospinal fluid (CSF) Aβ42/40 and Aβ42/total tau (T-tau). Plasma GFAP was measured at baseline and follow-up using Simoa technology. RESULTS: Baseline plasma GFAP could detect abnormal CSF Aβ42/40 and CSF Aβ42/T-tau with an AUC of 0.79 (95% CI 0.72-0.86) and 0.80 (95% CI 0.72-0.86), respectively. When also including APOE ε4 status as a predictor, the accuracy of the model to detect abnormal CSF Aβ42/40 status improved (AUC = 0.86, p = 0.02). Plasma GFAP predicted subsequent conversion to AD dementia with an AUC of 0.84 (95% CI 0.77-0.91), which was not significantly improved when adding APOE ε4 or age as predictors to the model. Longitudinal GFAP slopes for Aβ-positive and MCI who progressed to dementia (AD or other) were significantly steeper than those for Aβ-negative (p = 0.007) and stable MCI (p < 0.0001), respectively. CONCLUSION: Plasma GFAP can detect AD pathology in patients with MCI and predict conversion to AD dementia

Comparison of Brief Cognitive Tests and CSF Biomarkers in Predicting Alzheimer’s Disease in Mild Cognitive Impairment: Six-Year Follow-Up Study

INTRODUCTION: Early identification of Alzheimer's disease (AD) is needed both for clinical trials and in clinical practice. In this study, we compared brief cognitive tests and cerebrospinal fluid (CSF) biomarkers in predicting conversion from mild cognitive impairment (MCI) to AD. METHODS: At a memory clinic, 133 patients with MCI were followed until development of dementia or until they had been stable over a mean period of 5.9 years (range 3.2-8.8 years). The Mini-Mental State Examination (MMSE), the clock drawing test, total tau, tau phosphorylated at Thr(181) (P-tau) and amyloid-β(1-42) (Aβ(42)) were assessed at baseline. RESULTS: During clinical follow-up, 47% remained cognitively stable and 53% developed dementia, with an incidence of 13.8%/year. In the group that developed dementia the prevalence of AD was 73.2%, vascular dementia 14.1%, dementia with Lewy bodies (DLB) 5.6%, progressive supranuclear palsy (PSP) 4.2%, semantic dementia 1.4% and dementia due to brain tumour 1.4%. When predicting subsequent development of AD among patients with MCI, the cognitive tests classified 81% of the cases correctly (AUC, 0.85; 95% CI, 0.77-0.90) and CSF biomarkers 83% (AUC, 0.89; 95% CI, 0.82-0.94). The combination of cognitive tests and CSF (AUC, 0.93; 95% CI 0.87 to 0.96) was significantly better than the cognitive tests (p = 0.01) and the CSF biomarkers (p = 0.04) alone when predicting AD. CONCLUSIONS: The MMSE and the clock drawing test were as accurate as CSF biomarkers in predicting future development of AD in patients with MCI. Combining both instruments provided significantly greater accuracy than cognitive tests or CSF biomarkers alone in predicting AD

Alzheimer's disease biomarker discovery using SOMAscan multiplexed protein technology

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Insulin-like growth factors and related proteins in plasma and cerebrospinal fluids of HIV-positive individuals

BACKGROUND: Clinically significant dysregulation of the insulin-like growth factor (IGF) family proteins occurs in HIV-infected individuals, but the details including whether the deficiencies in IGFs contribute to CNS dysfunction are unknown. METHODS: We measured the levels of IGF1, IGF2, IGFBP1, IGFBP2, and IGF2 receptor (IGF2R) in matching plasma and cerebrospinal fluid (CSF) samples of 107 HIV+ individuals from CNS HIV Antiretroviral Therapy Effects Research (CHARTER) and analyzed their associations with demographic and disease characteristics, as well as levels of several soluble inflammatory mediators (TNFα, IL-6, IL-10, IL-17, IP-10, MCP-1, and progranulin). We also determined whether IGF1 or IGF2 deficiency is associated with HIV-associated neurocognitive disorder (HAND) and whether the levels of soluble IGF2R (an IGF scavenging receptor, which we also have found to be a cofactor for HIV infection in vitro) correlate with HIV viral load (VL). RESULTS: There was a positive correlation between the levels of IGF-binding proteins (IGFBPs) and those of inflammatory mediators: between plasma IGFBP1 and IL-17 (β coefficient 0.28, P = 0.009), plasma IGFBP2 and IL-6 (β coefficient 0.209, P = 0.021), CSF IGFBP1 and TNFα (β coefficient 0.394, P < 0.001), and CSF IGFBP2 and TNF-α (β coefficient 0.14, P < 0.001). As IGFBPs limit IGF availability, these results suggest that inflammation is a significant factor that modulates IGF protein expression/availability in the setting of HIV infection. However, there was no significant association between HAND and the reduced levels of plasma IGF1, IGF2, or CSF IGF1, suggesting a limited power of our study. Interestingly, plasma IGF1 was significantly reduced in subjects on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) compared to protease inhibitor-based therapy (174.1 ± 59.8 vs. 202.8 ± 47.3 ng/ml, P = 0.008), suggesting a scenario in which ART regimen-related toxicity can contribute to HAND. Plasma IGF2R levels were positively correlated with plasma VL (β coefficient 0.37, P = 0.021) and inversely correlated with current CD4+ T cell counts (β coefficient −0.04, P = 0.021), supporting our previous findings in vitro. CONCLUSIONS: Together, these results strongly implicate (1) an inverse relationship between inflammation and IGF growth factor availability and the contribution of IGF deficiencies to HAND and (2) the role of IGF2R in HIV infection and as a surrogate biomarker for HIV VL. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12974-015-0288-6) contains supplementary material, which is available to authorized users

Pathophysiological Mechanisms and Diagnostic Markers in Alzheimer’s Disease

Alzheimer’s disease (AD), the most common cause of dementia, is a growing concern. As the life expectancy increases across the globe, the number of affected people is estimated to reach 100 million by 2050. Efforts to develop effective treatments for humans have mostly been based on the assumption that a faulty homeostasis of beta amyloid (Aβ) is the triggering or the driving factor behind this condition. So far these efforts have failed, making a better understanding of other pathophysiological mechanisms behind this disease necessary in order to find new therapeutic approaches. The aim for this thesis was to explore such mechanisms. Besides changes typical of AD, these patients often show signs of vascular disease. In order to explore how white matter changes (WMLs) affects the course of disease, we analyzed CSF levels of phosphorylated tau (P-tau) and assessed WMLs on brain scans in healthy controls and patients with mild cognitive impairment. We found that a pathological level of P-tau and WMLs in the parietal lobes independently increased the risk of developing AD dementia, but that the risk was considerably higher for patients that had both. Next, we analyzed the CSF/plasma ratio of albumin, as a proxy for blood-brain barrier integrity, and found it to be increased in AD and other common dementias. This ratio was not associated with the APOE genotype, as had previously been suggested, or markers of Aβ load. Instead, we found it to be associated with diabetes mellitus and markers of microvascular damage in the brain. We then moved on from vascular factors to other mechanisms suggested in AD.The insulin-like growth factor (IGF) related system is implicated in regulating life-span and in growth-promotion and neuroprotection in the human nervous system. There are reports of changes to the IGF-related system in cognitive disorders. When we analyzed components of this system in healthy controls and patients with AD we found differences in CSF and blood plasma levels of IGF-II and some of its associated binding proteins, possibly reflecting an activated general response to neuronal damage. Lastly, we analyzed CSF biomarkers of synaptic degeneration (neurogranin) and microglial activation (YKL-40) in healthy controls, patients with mild cognitive impairment and patients with common dementias. We found the former to be selectively increased in AD dementia, whereas the latter was increased in both AD and frontotemporal dementia. However, these biomarkers did not improve the diagnostic accuracy of either prodromal AD or AD dementia when compared to established CSF biomarkers of AD. Nevertheless, we think they are useful, since they reflect other processes in AD than Aβ deposition and axonal damage. We hope that the results from this thesis has provided new insights into the pathophysiological mechanisms in AD and that they might suggest novel routes for exploring this complex condition

How do you elicit mathematics in concrete material?

Syftet med vårt examensarbete är att studera hur lärare ser på möjligheter att lyfta fram matematiken i undervisningen med laborativt material. Vi har valt att göra en kvalitativ undersökning med intervjuer av lärare. Resultatet av intervjuerna visar att de flesta lärare ansåg att eleverna ska komma på matematiken själva. De menade att lärarna ska vara tydliga med syftet och ha en genomtänkt tanke vid användning av spel och laborationer. De ansåg också att det var viktigt att vara positiv och entusiastisk gentemot spel och laborationer. De flesta lärarna tyckte att matematiken kommer automatiskt om eleverna är mogna för det som ska läras in. Lärarna hade olika uppfattningar om vilka förkunskaper de ansåg en lärare bör ha när de använder sig av laborativt material. De flesta ansåg att ett stort intresse och förståelse för matematik kan räcka. I diskussion kommer vi att diskutera det som fann intressant i slutsatsen och diskutera inledningen

Vi gir dem ikke opp En casestudie av organisering og lederstrategier i frafallsarbeidet i to videregående skoler

I denne oppgaven undersøker vi skolelederes erfaringer med frafallsarbeidet som gjøres i videregående skole. Vi valgte ut én videregående skole i to fylker og intervjuet fire skoleledere. Gjennom et casestudium fikk vi fram tette og virkelighetsnære beskrivelser. I studien benytter vi oss av utfyllende strategi for å håndtere teorimangfoldet. Kompleksiteten i skolen som organisasjon innebærer at vi hadde behov for flere innfallsvinkler for å forstå og analysere, i lys av teoretiske perspektiver. Viktige funn har vært at selv om nasjonale satsninger ikke så lett kan spores i klasserommene, har regionale og lokale tiltak har vist positive tegn, og enkelte fylker har en høyere andel elever med fullført og bestått enn andre. Selv om begge skolene benytter den samme modellen for identifisering, kartlegging og oppfølging (IKO), organiserer skolene frafallsarbeidet ulikt. Vi finner at aktørene i frafallsarbeidet er med på å påvirke strukturene i arbeidet. Videre ser vi forskjeller i støttetjenestenes organisering, og at tilbudet til elevene varierer fra fylke til fylke, og fra skole til skole. De to skolenes rektorer har ulik tilnærming til hvilke aktører som best håndterer frafallsarbeidet. Imidlertid har de et felles mål; å videreutvikle frafallsarbeidet for at flest mulig elever fullfører og består. Videre finner vi at skolens kontekst ser ut til å være avgjørende for lederstrategiene i frafallsarbeidet, blant annet er det elevgruppens behov som påvirker skoleledernes valg av strategier. Denne studien har implikasjoner for praksis og videre forskning, samt for den generelle verdidebatten om måling i skolen. Vi fant en verdirefleksjon hos skolelederne vi intervjuet, om at fullført og bestått-andelen er et øyeblikksbilde, og at deres menneskesyn favner videre enn som så, - elever kan nå sine mål, med mye støtte, og i eget tempo. Vi ser videre at mange av strategiene i frafallsarbeidet består av taus kunnskap, som med fordel kan gjøres eksplisitte, for å sikre en større kontinuitet. Skolene vi har studert, har gode resultater for fullført og bestått, på tross av ulike lokale strategier i frafallsarbeidet. Våre funn viser at strategiene omhandler arbeid med utvikling av en positiv skolekultur, med voksne som følger opp tett, og som har en variert verktøykasse i frafallsarbeidet