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The FAS phonemic fluency test is a commonly used neuropsychological test of executive function and processing speed. Although Norwegian discrete norms have been developed for the FAS test, American regression-based norms are frequently used by clinicians in Norway. However, language and cultural differences impact performance on the FAS test, and using foreign norms may not be appropriate. Moreover, while discrete norming relies on stratified subgroups of demographics, regression-based norming uses the entire sample to estimate the influence of demographics on performance and may thus improve normative estimates. Here we develop regression-based norms for the FAS phonemic fluency test based on n = 204 healthy Norwegian controls between the ages 40−84 from the Norwegian Dementia Disease Initiation cohort (DDI). We compare the proposed regression norms to published Norwegian discrete norms and American regression-based norms in an independent sample of n = 182 cognitively healthy adults reporting subjective cognitive decline (SCD). We found that years of education was the only significant predictor of FAS performance in our normative sample, accounting for 14.9% of the variance. Both the proposed regression-based norms and previously published discrete norms adequately adjusted for demographics in the independent sample. In contrast, the American norms underestimated the effect of education and overestimated the effect of age. While both the proposed Norwegian regression norms and the previously published discrete norms are suitable for use in Norway, the proposed regression norms may be less vulnerable to sub-stratification sample characteristics posed by discrete norming procedures, and thereby improve normative estimation.

Sammendrag Bakgrunn Motornevronsykdommene (MND) kjennetegnes av progressivt tap av motoriske nervebaner uten kurativ behandling og kort forventet levetid. I denne studien ville vi gjøre en journalgjennomgang av MND-populasjonen i Nord-Trøndelag fra 1984 til 2018 for å beskrive utviklingstrender hva gjelder oppfølging, behandlingstilbud og overlevelse. Materiale og metode 91 pasientjournaler ble inkludert for journalgjennomgang. Data ble innhentet gjennom Webbasert case report form og analysert i SPSS. MND-populasjonen ble delt i to kohorter, én for perioden 1984-2001 og én for perioden 2002-2018. Resultater Fra 1984-2001 var debutalder 62,6 (11) år, overlevelse 3 (2,9) år fra debut til død, 10 (24%) ble lungelegevurdert, 4 (9.5%) fikk behandling med non-invasiv ventilasjon (NIV) og 12 (28,6 %) fikk etablert perkutan endoskopisk gastrostomi (PEG). Fra 2002-2018 var debutalder 70,9 (11) år, overlevelse 1,8 (1,3) år fra debut til død, 21 (43 %) ble lungelegevurdert, 18 (36,7 %) fikk NIV og 29 (59,2 %) fikk PEG. Fortolkning På tross av bedre oppfølging, økt bruk av ventilasjonsstøtte og ernæring levde pasientene i perioden 2002-2018 kortere enn i 1984-2001.Vi vet at debutalder kan være prediktor for overlevelse hos pasienter med MND-sykdom, men resultatet må tolkes med forsiktighet på grunn av manglende morsdatoer på flere pasienter i kohort 1984-2001, samt flere langtidsoverlevere i samme kohort. Studien må bekreftes med større populasjon. Abstract Background Motor neuron disease (MND) is characterized by progressive loss of motor nerve pathways without curative treatment and with short life expectancy. In this study, we wanted to do a journal review of the MND population in Nord-Trøndelag from 1984 to 2018. We wanted to describe development trends in terms of follow-up, treatment and survival. Material and method 91 patient records were included for journal review. Data were collected through a web-based case report form and analyzed in SPSS. The MND population was divided into two cohorts, one for the period 1984-2001 and one for the period 2002-2018. Results From 1984-2001, the age of onset was 62.6 (11) years, 3 (2.9) years from onset to death, 10 (24%) were pulmonary assessed, 4 (9.5%) received treatment with non-invasive ventilation (NIV) and 12 (28.6%) had established percutaneous endoscopic gastrostomy (PEG). From 2002-2018, onset age was 70.9 (11) years, 1.8 (1.3) years from onset to death, 21 (43%) were pulmonary assessed, 18 (36.7%) received NIV and 29 (59, 2%) received PEG. Interpretation Despite better follow-up, increased use of ventilation support and nutrition, patients lived shorter in the period of 2002-2018 than from 1984-2001.We know that the onset age can be a predictor of survival in patients with MND, but the result must be interpreted with caution due to missing data on survival in the cohort from 1984-2001. The study also need to be confirmed with a larger population.

In the version of this Article initially published, the author list and affiliations were incomplete. Karl Heilbron and Adam Auton, both with 23andMe, Inc., have been added to the author list. Further, the location for the 23andMe Research Team, now reading “Sunnyvale, CA” initially appeared as Mountain View, CA. The changes have been made to the online version of the paper.

In the version of this article initially published, in the phase 3 meta-analysis, the UK Biobank results were overweighed with a slightly larger (5%) N, thus resulting in a minimal underestimation of effect sizes and in P values marginally less significant than their actual values. Because the differences were on the order of the ninth decimal, there is no notable effect on the results or the conclusions drawn. The summary statistics have been updated accordingly at https://ctg.cncr.nl/software/summary_statistics. The Data availability statement has been updated to include the new URL in the HTML and PDF versions of the article.

“The authors would like to thank the Norwegian Dementia Genetics Network (DemGene), the European DLB Consortium (E-DLB), Dementia Genetics Spanish Consortium (DEGESCO) and Genomic Research at Fundació ACE (GR@ACE) Consortium. Fundació ACE would like to thank patients and controls who participated in this project. We are indebted to private donors for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). The study was founded by the Research Council of Norway, Norwegian Regional Health Authorities and Norwegian Health Association and 237250/EU/JPND (APGeM). The Cohort 2 results were generated with the assistance of financial support of grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). GR@ACE project has been funded by Fundación bancaria “La Caixa”, Grifols SA, Fundació ACE. The funding sources did not in any way affect the results or presentation of the results.” should read: “The authors would like to thank the Norwegian Dementia Genetics Network (DemGene), the European DLB Consortium (E-DLB), Dementia Genetics Spanish Consortium (DEGESCO) and Genomic Research at Fundació ACE (GR@ACE) Consortium. Fundació ACE would like to thank patients and controls who participated in this project. We are indebted to private donors for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). The study was founded by the Research Council of Norway, Norwegian Regional Health Authorities and Norwegian Health Association and 237250/EU/JPND (APGeM). The Cohort 2 results were generated with the assistance of financial support of grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). GR@ACE project has been funded by Fundación bancaria “La Caixa”, Grifols SA, Fundació ACE. The funding sources did not in any way affect the results or presentation of the results. This paper represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author and not necessarily those of the NIHR or the Department of Health and Social Care”.

Background Kallikrein 6 (KLK6) is known to be an age-related protease expressed at high levels in the central nervous system. It was previously shown to be involved in proteolysis of extracellular proteins implicated in neurodegenerative diseases such as Alzheimer’s disease (AD), prompting validation of KLK6 as a potential biomarker of disease. However, analyses of both plasma and cerebrospinal fluid (CSF) levels of KLK6 in patients with AD have been inconclusive. We present a detailed analysis of KLK6 in plasma and CSF in two separate cohorts in a cross-sectional and a longitudinal clinical setting. Methods The cross-sectional cohort included control subjects without dementia and patients with AD, and the longitudinal cohort included patients with MCI and patients with AD followed over a 2-year period. Plasma and CSF levels of KLK6 were quantified by use of a previously developed and validated enzyme-linked immunosorbent assay. Statistical analyses were performed to compare KLK6 levels between diagnostic groups and to identify potential associations between KLK6 level, age, apolipoprotein E (APOE) genotype, total apoE level and the classical CSF AD biomarkers. Results In the cross-sectional setting, KLK6 levels in plasma but not in CSF were significantly higher in the AD group than in control subjects. CSF but not plasma KLK6 levels were positively correlated with age in both the cross-sectional and longitudinal settings. In both cohorts, the CSF KLK6 levels were significantly and positively correlated with the CSF levels of core AD biomarkers. Total plasma and CSF apoE levels were positively associated with KLK6 in the cross-sectional study. Finally, during the 2-year monitoring period of the longitudinal cohort, CSF KLK6 levels increased with disease progression over time in the investigated patient groups. Conclusions In two separate cohorts we have confirmed the previously reported correlation between age and CSF levels of KLK6. Increased plasma KLK6 levels in patients with AD with a more advanced disease stage suggest KLK6 as a potential biomarker in patients with AD with more severe dementia. Significant correlations between KLK6 levels and core CSF AD biomarkers suggest molecular links between KLK6 and AD-related pathological processes. © The Author(s). 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

a) Observed group mean values (± SD) for α-synuclein at inclusion (baseline), and after one and two years, and b) predicted mean value (95 % CI) at baseline, together with estimated mean change (95 % CI) from baseline values.1 (DOCX 14 kb)

Mean levels of α-synuclein in CSF at inclusion for carriers and non- carriers of APOE ε4. (DOCX 12 kb)

The aims of this dissertation were to investigate alcohol-related seizures in clinical neurological practice. We wanted to assess the extent of this problem, to classify the seizures, and to investigate methods to improve the clinical diagnosis of such seizures. We propose an arbitrary but simple and reproducible way of diagnosing alcohol-related seizures and alcohol withdrawal seizures. Papers I and II relate to seizure classification and the extent of the problem in relation to the level and weekly pattern of alcohol use. Paper III investigates the performance of various biological markers as aids in the diagnosis of alcohol-related seizures. Paper IV explores pitfalls in the result interpretation for two methods for detection of CDT in patients with neurological disorders. Paper V investigates the utility of standard EEG for the identification of alcohol-related seizures. Even though the general alcohol consumption in our region is low, every third patient with an epileptic seizure leading to hospitalisation had hazardous alcohol consumption. Evidence of focal lesions or focal seizure start was found in a high proportion of alcohol-related seizures. All such seizures were secondarily generalized and thus, we challenge the establishment impression that the vast majority of alcohol-related seizures are primarily generalized. Binge drinking (more than six drinks for men or four drinks for women, in a single drinking occasion) was common, but had little influence on seizure susceptibility or timing of seizures. In contrast to prior knowledge, we found that in some patients there was no time lag from cessation of drinking to the occurrence of a seizure, but falling intake levels prior to withdrawal seizures were demonstrated. This indicates that a state of relative withdrawal while still drinking may be sufficient to induce a seizure. Carbohydrate-deficient transferring (CDT) is the most accurate biomarker for alcohol use and good adjunct to the diagnosis of alcohol-related seizures, but its accuracy does not compete with a good clinical investigation. Generally poor accuracy should be expected for fertile women. Women on enzyme-inducing antiepileptic drugs who drink no or little alcohol seem to be at risk of having false positive CDT. Other variables associated with increased CDT were low body mass index, or having total transferring levels outside normal range. A definitely abnormal EEG suggests epilepsy or symptomatic seizures unrelated to alcohol use. The predictive value of a normal EEG is limited, but the typical post-ictal finding in alcohol-related seizures is nevertheless a normal low-amplitude EEG record. The best method for identification of alcohol-related seizures is a clinical work-up based on a thorough medical history. The Alcohol Use Disorders Identification Test (AUDIT) provides a reliable measure of drinking habits. CDT is a good supplement to the clinical diagnosis when there is doubt, if factors associated with false-positive values are appreciated. The diagnostic value of EEG is limited. dr.med. dr.med.