Disclosing or concealing multiple sclerosis in the workplace: two sides of the same coin-insights from a Swedish population-based survey.

Background: People with multiple sclerosis (PwMS) face health and social challenges of living with a chronic and potentially disabling condition. To disclose or conceal MS at work may critically affect individuals' work situation, career opportunities, and health. PwMS may experience a dilemma when assessing if the possible benefits of disclosing the diagnosis outweigh the possible risks. However, concealing in the long-term may have health implications and prevent opportunities for support and work adjustments. Few studies have examined what drives PwMS to disclose or conceal MS at work and the consequences of these ways of managing MS. Objectives: To explore the reasons PwMS report for disclosing and/or concealing their MS diagnosis in the workplace, as well as the consequences they have experienced. Methods: A web-based survey of PwMS was conducted in 2021. All individuals aged 20-50 listed in the Swedish MS registry were invited to participate. The response rate was 52% and among these participants, 3,810 (86%) completed questions regarding workplace disclosure and/or concealment of MS. Free-text responses on these topics were analyzed using inductive content analysis. Results: It was common to disclose MS in the workplace (85%). Identified drivers for disclosure and concealment related to four categories: Work-related, Social, Personal and Circumstantial. Work-related drivers focused on employment or protecting one's career, and changing one's work situation versus maintaining it. Social drivers included the need for support, addressing or preventing stigma, and being considerate of others. Personal drivers were linked to moral values/personal beliefs and processing of the diagnosis. Circumstantial drivers related to involuntary or unforeseen events, timing factors, one's medical condition and external opinion/advice. Identified consequences for disclosure and concealment related to three categories: Work-life, Social, and Personal. Work-life consequences included work arrangements, and career opportunities. Social consequences were linked to MS awareness, stigma, interactions and social support, as well as dynamics of work relationships. Personal consequences involved levels of disease acceptance, and attitudes toward managing MS. Conclusion: PwMS often described the question of disclosure as challenging and navigated it with caution, as both disclosure and concealment can yield favorable and unfavorable outcomes.

Recent trends in disease-modifying therapy use and associated sickness absence and disability pension among people with multiple sclerosis in Sweden.

BACKGROUND: Disease-modifying therapies (DMTs) have led to improved health and work productivity among people with multiple sclerosis (PwMS). OBJECTIVES: To describe trajectories of recent DMT use and their association with sickness absence and/or disability pension (SADP) among PwMS in Sweden. METHODS: A longitudinal register-based study was conducted among 1395 PwMS with treatment start in 2014/2015. While DMT use over 5 years was assessed using sequence analysis resulting in four clusters, a 7-year (Y-2 toY4) trend of SADP was analyzed using zero-inflated negative binomial regression. RESULTS: Four clusters of DMT use trajectories were identified: long-term non-high-efficacy (483, 34.6%), long-term high-efficacy (572, 41%), escalation (221, 15.8%), and discontinuation (119, 8.5%). Progressive MS and higher expanded disability status scale scores were associated with the escalation, long-term high-efficacy, or discontinuation clusters. PwMS in the long-term high-efficacy and escalation clusters had higher likelihood of being on SADP. However, PwMS initiating high-efficacy DMTs demonstrated steeper decline in SADP than others. CONCLUSION: Using sequence analysis, this study showed recent DMT use trajectories among PwMS where initiation of high-efficacy DMTs has become more common. The trend of SADP was stable and lower in those using non-high-efficacy DMTs and larger improvements were shown in those initiating high-efficacy DMTs.

Revealing Sexual Dimorphism in Prolactin Regulation From Early Postnatal Development to Adulthood in Murine Models.

Serum prolactin (PRL) levels exhibit a gradual rise both in male and female rats from birth to adulthood, with females consistently displaying higher levels compared to age-matched males. This pattern has traditionally been attributed to the development and maturation of endocrine and neuroendocrine networks responsible for regulating PRL synthesis and secretion. However, the effect of dopamine (DA), which acts as an inhibitory factor on lactotroph function, also increases from birth to puberty, particularly in females. Nonetheless, the secretion of PRL remains higher in females compared to males. On the other hand, the observed sex differences in serum PRL levels during early postnatal development cannot be attributed to the influence of estradiol (E2). While serum E2 levels gradually increase after birth, only after 45 days of life do the disparities in E2 levels between females and males become evident. These observations collectively suggest that neither the maturation of hypothalamic DA regulation nor the rise in E2 levels can account for the progressive and sustained elevation in serum PRL levels and the observed sexual dimorphism during postnatal development. This review highlights the importance of recent discoveries in animal models that shed light on inhibitory mechanisms in the control of PRL secretion within the pituitary gland itself, that is intrapituitary mechanisms, with a specific emphasis on the role of transforming growth factor ß1 and activins in PRL secretion.

Work Adjustments by Types of Occupations Amongst People with Multiple Sclerosis: A Survey Study.

PURPOSE: To explore the occurrence of work adjustments for people with multiple sclerosis (MS) across types of occupations (managerial, office, and manual workers). METHODS: All working-aged (20-50 years) residents in Sweden diagnosed with MS were invited to participate in a web-based survey in 2021. Responses were linked to individual-level nationwide registers. Descriptive analyses were conducted to compare sociodemographic and clinical variables across occupations as well as other responses. The odds ratio of having any adjustment at work was determined using multinomial logistic regression. RESULTS: From all 4412 respondents (52% response rate), 3313 employees were included. The majority were women (72%) and had low (24.2%) or mild disease severity (44.7%). Nevertheless, different work adjustments across occupations were observed. Compared to the other occupations, office workers reported more invisible symptoms, more work adjustments and considered adapted schedules as the most important adjustment. On the contrary, more managers reported having no limiting symptoms and consequently, disclosed their diagnosis less often. They also reported having fewer work adjustments and more opportunities to modify their work than office and manual workers. Manual workers had a higher likelihood to report needing more support at work than office workers and managers. Further, a higher likelihood of having work adjustments was associated with progressive MS, higher MS severity, and invisible symptoms. CONCLUSION: A more severe clinical profile of MS was associated with having work adjustments. The physical demands and responsibilities of an occupation play an important role when requesting and getting work adjustments amongst employees with MS.

Gender differences in earnings among people with multiple sclerosis and associations with type of occupation and family composition: A population-based study with matched references.

Gender differences in earnings exist worldwide. Gender segregation or familial status have been previously stated as possible explanations for these differences as well as health differences between women and men. Women are diagnosed with multiple sclerosis (MS) as twice much as men. Moreover, MS limitations may affect the work capacity of people with MS (PwMS) implying a reduction in their earnings. We aimed to explore gender differences in earnings among people with MS and without MS and between groups of those diagnosed while also considering types of occupation and family composition, and how these possible differences relate to sickness absence (SA) and disability pension (DP). We conducted a population-based cohort study in Sweden with microdata from several nationwide registers. PwMS aged 19-57 years (n = 5128) living in Sweden and 31,767 matched references from the population without MS. Outcome measures included earnings, number of SA and DP days combined (SA/DP). A four-way weighted least-squares analysis of covariance was performed to explore the associations of gender, MS, type of occupation, and family composition with earnings. Risk of SA and DP days was assessed with logistic regression. Overall, and across all occupations, women earned less than men, although less so among managers with MS. Annual gender differences in earnings were larger if living with children at home compared to not living with children. Nevertheless, these gender differences decreased after adjusting for SA/DP, both among PwMS and references. PwMS had considerably more SA/DP days than references. Women also had more SA/DP days than men. We observed that working women earned less than working men, and that gender differences in earnings were present in all occupations, although less evident among PwMS in managerial positions. The combination of gender, occupation, family composition, and MS, was associated with earnings, even when adjusting for the number of SA and DP days.

Sex-specific regulation of prolactin secretion by pituitary activins in postnatal development.

Serum prolactin increases from birth to adulthood in rats, being higher in females from birth. The maturation of hypothalamic/gonadal prolactin-releasing and -inhibiting factors does not explain some sex differences observed. During the first weeks of life, prolactin secretion increases, even when lactotrophs are isolated in vitro, in the absence of those controls, suggesting the participation of intra-pituitary factors in this control. The present work aimed to study the involvement of pituitary activins in the regulation of prolactin secretion during post-natal development. Sex differences were also highlighted. Female and male Sprague-Dawley rats at 11, 23 and 45postnatal days were used. Pituitary expression of activin subunits and activin receptors was maximum in p11 female pituitaries, being even higher than that observed in males. Those expressions decrease with age in females, and then the gender differences disappear at p23. Inhbb expression strongly increases at p45 in males, being the predominant subunit in this sex in adulthood. Activin inhibition of prolactin is mediated by the inhibition of Pit-1 expression. This action involves not only the canonical pSMAD pathway but also the phosphorylation of p38MAPK. At p11, almost all lactotrophs express p-p38MAPK in females, and its expression decreases with age with a concomitant increase in Pit-1. Our findings suggest that the inhibitory regulation of pituitary activins on prolactin secretion is sex specific; this regulation is more relevant in females during the first week of life and decreases with age; this intra-pituitary regulation is involved in the sex differences observed in serum prolactin levels during postnatal development.

Association of Chronic Kidney Disease With Plasma NfL and Other Biomarkers of Neurodegeneration: The H70 Birth Cohort Study in Gothenburg.

BACKGROUND AND OBJECTIVES: Studies associate chronic kidney disease (CKD) with neurodegeneration. This study investigated the relationship between kidney function, blood, CSF, and structural brain MRI markers of neurodegeneration in a sample including individuals with and without CKD. METHODS: Participants from the Gothenburg H70 Birth Cohort Study, with data on plasma neurofilament light (P-NfL), estimated glomerular filtration rate (eGFR), and structural brain MRI were included. Participants were invited to also have the CSF collected. The primary endpoint of this study was to determine any association between CKD and P-NfL. Secondary endpoints included cross-sectional associations between CKD, eGFR, and CSF-derived and MRI-derived markers of neurodegeneration and Alzheimer disease (AD) pathology (MRI: cortical thickness, hippocampal volume, lateral ventricle volume, and white matter lesion volume; CSF: ß-amyloid (Aß) 42, Aß42/40, Aß42/p-tau, t-tau, p-tau, and NfL). Participants with P-NfL and eGFR at baseline were re-examined on eGFR, 5.5 (5.3-6.1) years (median; IQR) after the first visit, and the predictive value of P-NfL levels on incident CKD was estimated longitudinally, using a Cox proportional hazards model. RESULTS: We included 744 participants, 668 without CKD (age 71 [70-71] years, 50% males) and 76 with CKD (age 71 [70-71] years, 39% males). Biomarkers from the CSF were analyzed in 313 participants. A total of 558 individuals returned for a re-examination of eGFR (75% response rate, age 76 [76; 77] years, 48% males, 76 new cases of CKD). Participants with CKD had higher P-NfL levels than those with normal kidney function (median; 18.8 vs 14.1 pg/mL, p < 0.001), while MRI and CSF markers were similar between the groups. P-NfL was independently associated with CKD after adjustment for confounding variables, including hypertension and diabetes (OR; 3.231, p < 0.001), in a logistic regression model. eGFR and CSF Aß 42/40: R = 0.23, p = 0.004 correlated in participants with Aß42 pathology. P-NfL levels in the highest quartile were associated with incident CKD at follow-up (HR; 2.39 [1.21: 4.72]). DISCUSSION: In a community-based cohort of 70-year olds, P-NfL was associated with both prevalent and incident CKD, while CSF and/or imaging measures did not differ by CKD status. Participants with CKD and dementia presented similar levels of P-NfL.

Self-reported restrictions in different life domains and associated factors among people with multiple sclerosis in Sweden.

BACKGROUND AND PURPOSE: The heterogeneous symptoms of multiple sclerosis (MS) can considerably impact the lives of people with MS (PwMS). The aim of this study was to describe the extent of restrictions in different life domains that PwMS experience in relation to their symptoms and level of disability. METHODS: A cross-sectional survey was conducted among working-age PwMS in Sweden. The 4052 participants who answered the questions on restrictions in work and private life domains (family, leisure activities, and contact with friends/acquaintances) were included. Predictors of restrictions in the four domains were determined through multinomial logistic regression. RESULTS: Approximately one-third of the PwMS reported no restrictions in the domains of work (35.7%), family (38.7%), leisure activities (31.1%) or contact with friends/acquaintances (40.3%), the remaining participants reported moderate to severe restrictions. Tiredness/fatigue was the most commonly reported most-limiting symptom (49.5%). PwMS with Expanded Disability Status Scale (EDSS) scores of zero reported restrictions in life domains ranging from 39.6% (friends/acquaintances) to 45.7% (leisure activities). Age, sex, education, type of living area, MS type, type of most-limiting symptom, and EDSS score predicted restrictions in work and private life domains. CONCLUSIONS: Most PwMS reported similar levels of restrictions in both their work and private lives. Restrictions in these life domains were also reported by PwMS with low disability levels (EDSS = 0) and were often associated with invisible symptoms such as fatigue. Even in a contemporary MS cohort, close to 90% of PwMS report limitations due to MS.

Trajectories of disease-modifying therapies and associated sickness absence and disability pension among 1923 people with multiple sclerosis in Sweden.

BACKGROUND: There is limited information on the trajectories of disease-modifying therapy (DMT) use and their association with sickness absence and/or disability pension (SADP) among people with multiple sclerosis (PwMS). The objective of the study was to identify trajectories of DMT use over 10 years among PwMS, identify sociodemographic and clinical factors associated with the trajectories, and to assess the association between identified trajectories and SADP days. METHODS: A longitudinal register-based study was conducted, on a prospective data set linked across six nationwide registers, assessing treatment courses of PwMS with DMTs for the 10 years following multiple sclerosis (MS) onset. The study included 1923 PwMS with MS onset in 2007-2010, when aged 19-56 years. In each 6-month-period, their treatment was categorized as before treatment, high-efficacy, non-high-efficacy, or no DMT. Sequence analysis was performed to identify sequences of the treatment categories and cluster them into different DMT trajectories. Cluster belonging, in relation to demographic and clinical characteristics, was assessed through log-multinomial regression analysis. The association of trajectories/cluster-belonging with SADP net days was assessed using generalized estimating equation (GEE) models. RESULTS: Cluster analyses identified 4 trajectories of DMT use: long-term non-high-efficacy DMTs (38.6%), escalation to high-efficacy DMTs (31.2%), delayed start and escalation to high-efficacy DMTs (15.4%), and discontinued/ no DMT (14.2%). Age, MS type, expanded disability status scale (EDSS) score and the number of DMT switches were associated with cluster belonging. The youngest age group (18-25) were more likely to be in the escalation to high-efficacy cluster. People with primary progressive MS were more likely to be in the delayed start or discontinued/ no DMT cluster. Higher EDSS scores were associated to being in the other three clusters than in the long-term non-high-efficacy DMTs cluster. Higher number of DMT switches were associated with being in the escalation to high-efficacy DMTs cluster but less likely to be in the delayed start or discontinued/ no DMT clusters. Descriptive analyses showed a trend of fewer mean SADP days among PwMS using non-high-efficacy DMT than the other clusters about 9 years after onset. PwMS in the escalation to high-efficacy and discontinued/no DMT clusters had more SADP days. PwMS in the delayed start and escalation to high-efficacy DMTs cluster, started with fewer SADP days which increased over time. SADP days adjusted through GEE models showed trends comparable with the descriptive analysis. CONCLUSION: This study described the long-term real-world trajectories of DMT use among PwMS in Sweden using sequence analysis and showed the association of the trajectories with SADP days as well as sociodemographic and clinical characteristics.

Excess costs of multiple sclerosis: a register-based study in Sweden.

BACKGROUND AND OBJECTIVE: Population-based estimates of the socioeconomic burden of multiple sclerosis (MS) are limited, especially regarding primary healthcare. This study aimed to estimate the excess costs of people with MS that could be attributed to their MS, including primary healthcare. METHODS: An observational study was conducted of the 2806 working-aged people with MS in Stockholm, Sweden and 28,060 propensity score matched references without MS. Register-based resource use was quantified for 2018. Annual healthcare costs (primary, specialised outpatient, and inpatient healthcare visits along with prescribed drugs) and productivity losses (operationalised by sickness absence and disability pension days) were quantified using bottom-up costing. The costs of people with MS were compared with those of the references using independent t-tests with bootstrapped 95% confidence intervals (CIs) to isolate the excess costs of MS from the mean difference. RESULTS: The mean annual excess costs of MS for healthcare were €7381 (95% CI 6991-7816) per person with MS with disease-modifying therapies as the largest component (€4262, 95% CI 4026-4497). There was a mean annual excess cost for primary healthcare of €695 (95% CI 585-832) per person with MS, comprising 9.4% of the excess healthcare costs of MS. The mean annual excess costs of MS for productivity losses were €13,173 (95% CI 12,325-14,019) per person with MS, predominately from disability pension (79.3%). CONCLUSIONS: The socioeconomic burden of MS in Sweden from healthcare consumption and productivity losses was quantified, updating knowledge on the cost structure of the substantial excess costs of MS.

Association of Cerebrovascular and Alzheimer Disease Biomarkers With Cholinergic White Matter Degeneration in Cognitively Unimpaired Individuals.

BACKGROUND AND OBJECTIVES: Several pathologic processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers toward the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals. METHODS: The contribution of amyloid and tau pathology was assessed through CSF levels of the Aß42/40 ratio and phosphorylated tau (p-tau). CSF Aß38 levels were also measured. Cerebrovascular pathology was assessed using automatic segmentations of WM lesions (WMLs) on MRI. Cholinergic WM projections (i.e., cingulum and external capsule pathways) were modeled using tractography based on diffusion tensor imaging data. Sex and APOE ε4 carriership were also included in the analysis as variables of interest. RESULTS: We included 203 cognitively unimpaired individuals from the H70 Gothenburg Birth Cohort Studies (all individuals aged 70 years, 51% female). WM lesion burden was the most important contributor to the degeneration of both cholinergic pathways (increase in mean square error [IncMSE] = 98.8% in the external capsule pathway and IncMSE = 93.3% in the cingulum pathway). Levels of Aß38 and p-tau also contributed to cholinergic WM degeneration, especially in the external capsule pathway (IncMSE = 28.4% and IncMSE = 23.4%, respectively). The Aß42/40 ratio did not contribute notably to the models (IncMSE<3.0%). APOE ε4 carriers showed poorer integrity in the cingulum pathway (IncMSE = 21.33%). Women showed poorer integrity of the external capsule pathway (IncMSE = 21.55%), which was independent of amyloid status as reflected by the nonsignificant differences in integrity when comparing amyloid-positive vs amyloid-negative women participants (T201 = -1.55; p = 0.123). DISCUSSION: In cognitively unimpaired older individuals, WMLs play a central role in the degeneration of cholinergic pathways. Our findings highlight the importance of WM lesion burden in the elderly population, which should be considered in the development of prevention programs for neurodegeneration and cognitive impairment.

Sex-specific Regulation of Prolactin Secretion by Pituitary Bradykinin Receptors.

Sex differences in the control of prolactin secretion are well documented. Sex-related differences in intrapituitary factors regulating lactotroph function have recently attracted attention. Sex differences in prolactinoma development are well documented in clinic, prolactinomas being more frequent in women but more aggressive in men, for poorly understood reasons. Kallikrein, the enzyme releasing kinins has been found in the pituitary, but there is no information on pituitary kinin receptors and their function. In the present work, we characterized pituitary bradykinin receptors (BRs) at the messenger RNA and protein levels in 2 mouse models of prolactinoma, Drd2 receptor gene inactivation and hCGß gene overexpression, in both males and females, wild type or genomically altered. BR B2 (B2R) accounted for 97% or more of total pituitary BRs in both models, regardless of genotype, and was present in lactotrophs, somatotrophs, and gonadotrophs. Male pituitaries displayed higher level of B2R than females, regardless of genotype. Pituitary B2R gene expression was downregulated by estrogen in both males and females but only in females by dopamine. Activation of B1R or B2R by selective pharmacological agonists induced prolactin release in male pituitaries but inhibited prolactin secretion in female pituitaries. Increased B2R content was observed in pituitaries of mutated animals developing prolactinomas, compared to their respective wild-type controls. The present study documents a novel sex-related difference in the control of prolactin secretion and suggests that kinins are involved, through B2R activation, in lactotroph function and prolactinoma development.

Self-employment, sickness absence, and disability pension in multiple sclerosis.

OBJECTIVES: Early withdrawal from work is common among people with multiple sclerosis (PwMS). However, little is known about how this is influenced by the type of employment. The aims were to explore the distributions of self-employed and other types of employment (employed or no earnings from work) before and after MS diagnosis and its associations with sickness absence (SA) and disability pension (DP) among PwMS and matched references without MS. MATERIALS & METHOD: A 6-year longitudinal cohort study of 2779 individuals diagnosed with MS in 2008-2012 when aged 20-59 and of 13,863 matched individuals without MS from Sweden's population was conducted. Hazard ratios (HR) of >180 SA and/or DP days/year were compared by employment status among PwMS and references using Cox proportional hazard models with 95% confidence intervals (CI). RESULTS: Most had no SA or DP. Nevertheless, PwMS had higher SA and DP levels compared with references. PwMS had a higher likelihood to reach >180 days of SA (HR = 4.89, 95% CI = 4.43-5.40) or days of DP (HR = 6.31, 95% CI = 5.46-7.30), irrespective of the employment status. Self-employed references had less likelihood for >180 SA days than employed references. However, self-employed and employed PwMS had a similar likelihood for >180 SA days. Transitions of employees to self-employment were infrequent among PwMS (1.7%) and references (2.6%). CONCLUSIONS: PwMS transit to SA and DP to a higher extent than references. In contrast to individuals without MS, self-employed PwMS had similar SA levels to employed PwMS. Switching to self-employment was not a predominant choice for people recently diagnosed with MS.

Oophorectomy improves pituitary activin inhibitory function preventing lactotroph hyperplasia development.

Among pituitary adenomas, prolactinomas are the most frequently diagnosed (about 50%). Dopamine agonists are generally effective in the treatment of prolactinomas. However, a subset of about 25% of patients does not respond to these agents. The management of drug-resistant prolactinomas remains a challenge for endocrinologists and new inhibitory treatments are needed. Pituitary activins inhibit lactotroph function. Its expression and action were found reduced in animal models of lactotroph hyperplasia (female mice overexpressing the B subunit of the human chorionic gonadotrophin and female mice knockout for dopamine receptor type 2). In these models, an oophorectomy avoids prolactinoma development. Hormonal replacement with oestradiol and/or progesterone is not enough to reach the tumor size observed in transgenic females. We postulated that the loss of gonadal inhibins after an oophorectomy contributes to prevent hyperplasia development. Here, we demonstrated that an oophorectomy at 2 months age recovers the following in adulthood: (i) pituitary activin expression, (ii) activin receptor expression specifically in lactotroph population, (iii) activin biological activity in lactotrophs with a concomitant reduction of Pit-1 expression. To summarize, when an oophorectomy is performed, inhibins are lost and the inhibitory action of pituitary activins on lactotroph population is recovered, helping to prevent lactotroph hyperplasia development. These results emphasize the importance of the inhibitory action of activins on lactotroph function, positioning activins as a good therapeutic target for the treatment of resistant prolactinomas.

Plasma and CSF NfL are differentially associated with biomarker evidence of neurodegeneration in a community-based sample of 70-year-olds.

Neurofilament light protein (NfL) in cerebrospinal fluid (CSF) and plasma (P) are suggested to be interchangeable markers of neurodegeneration. However, evidence is scarce from community-based samples. NfL was examined in a small-scale sample of 287 individuals from the Gothenburg H70 Birth cohort 1944 study, using linear models in relation to CSF and magnetic resonance imaging (MRI) biomarker evidence of neurodegeneration. CSF-NfL and P-NfL present distinct associations with biomarker evidence of Alzheimer's disease (AD) pathology and neurodegeneration. P-NfL was associated with several markers that are characteristic of AD, including smaller hippocampal volumes, amyloid beta (Aß)42, Aß42/40, and Aß42/t-tau (total tau). CSF-NfL demonstrated associations with measures of synaptic and neurodegeneration, including t-tau, phosphorylated tau (p-tau), and neurogranin. Our findings suggest that P-NfL and CSF-NfL may exert different effects on markers of neurodegeneration in a small-scale community-based sample of 70-year-olds.

Trajectories of sickness absence and disability pension days among people with multiple sclerosis by type of occupation.

BACKGROUND: Multiple sclerosis (MS) can impact working life, sickness absence (SA) and disability pension (DP). Different types of occupations involve different demands, which may be associated with trajectories of SA/DP among people with MS (PwMS). OBJECTIVES: To explore, among PwMS and references, if SA/DP differ according to type of occupation. Furthermore, to examine how trajectories of SA/DP days are associated with type of occupation among PwMS. METHODS: A longitudinal nationwide Swedish register-based cohort study was conducted, including 6100 individuals with prevalent MS and 38,641 matched references from the population. Trajectories of SA/DP were identified with group-based trajectory modelling. Multinomial logistic regressions were estimated for associations between identified trajectories and occupations. RESULTS: Increase of SA/DP over time was observed in all occupational groups, in both PwMS and references, with higher levels of SA/DP among PwMS. The lowest levels of SA/DP were observed among managers. Three trajectory groups of SA/DP were identified: Persistently Low (55.2%), Moderate Increasing (31.9%) and High Increasing (12.8%). Managers and those working in Science & Technology, and Economics, Social & Cultural were more likely to belong to the Persistently Low group. CONCLUSION: Results suggest that type of occupation plays a role in the level and course of SA/DP.

Swedish Normative Data for Mindmore: A Comprehensive Cognitive Screening Battery, Both Digital and Self-Administrated.

OBJECTIVE: Cognitive impairment is a key element in most mental disorders. Its objective assessment at initial patient contact in primary care can lead to better adjusted and timely care with personalised treatment and recovery. To enable this, we designed the Mindmore self-administrative cognitive screening battery. What is presented here is normative data for the Mindmore battery for the Swedish population. METHOD: A total of 720 healthy adults (17 to 93 years) completed the Mindmore screening battery, which consists of 14 individual tests across five cognitive domains: attention and processing speed, memory, language, visuospatial functions and executive functions. Regression-based normative data were established for 42 test result measures, investigating linear, non-linear and interaction effects between age, education and sex. RESULTS: The test results were most affected by age and to a lesser extent by education and sex. All but one test displayed either linear or accelerated age-related decline, or a U-shaped association with age. All but two tests showed beneficial effects of education, either linear or subsiding after 12 years of educational attainment. Sex affected tests in the memory and executive domains. In three tests, an interaction between age and education revealed an increased benefit of education later in life. CONCLUSION: This study provides normative models for 14 traditional cognitive tests adapted for self-administration through a digital platform. The models will enable more accurate interpretation of test results, hopefully leading to improved clinical decision making and better care for patients with cognitive impairment.

Sex differences in CSF biomarkers for neurodegeneration and blood-brain barrier integrity.

INTRODUCTION: As cerebrospinal fluid (CSF) neurofilament light protein (NfL) and the CSF/serum albumin ratio (QAlb) are used in the clinical routine, the impact of demographic factors on these biomarkers is important to understand. METHODS: Participants were derived from two Swedish samples: the population-based H70 Study (n = 308, age 70) and a clinical routine cohort (CSF NfL, n = 8995, QAlb, n = 39252, age 0 to 95). In the population-based study, QAlb and NfL were examined in relation to sex, cardiovascular risk factors, and cerebral white matter lesions (WMLs). In the clinical cohort, QAlb and NfL sex differences were tested in relation to age. RESULTS: Men had higher QAlb and NfL concentrations and had higher QAlb and NfL concentrations from adolescence throughout life. NfL was not related to WML, but QAlb correlated positively with WMLs. DISCUSSION: The CSF NfL sex difference could not be explained by vascular pathology. Future studies should consider using different reference limits for men and women.

Effects of amyloid pathology and the APOE ε4 allele on the association between cerebrospinal fluid Aß38 and Aß40 and brain morphology in cognitively normal 70-years-olds.

The association between cerebrospinal fluid (CSF) amyloid beta (Aß) Aß38 or Aß40 and brain grey- and white matter integrity is poorly understood. We studied this in 213 cognitively normal 70-year-olds, and in subgroups defined by presence/absence of the APOE ε4 allele and Aß pathology: Aß-/APOE-, Aß+/APOE-, Aß-/APOE+ and Aß+/APOE+. CSF Aß was quantified using ELISA and genotyping for APOE was performed. Low CSF Aß42 defined Aß plaque pathology. Brain volumes were assessed using Freesurfer-5.3, and white matter integrity using tract-based statistics in FSL. Aß38 and Aß40 were positively correlated with cortical thickness, some subcortical volumes and white matter integrity in the total sample, and in 3 of the subgroups: Aß-/APOE-, Aß+/APOE- and Aß-/APOE+. In Aß+/APOE+ subjects, higher Aß38 and Aß40 were linked to reduced cortical thickness and subcortical volumes. We hypothesize that production of all Aß species decrease in brain regions with atrophy. In Aß+/APOE+, Aß-dysregulation may be linked to cortical atrophy in which high Aß levels is causing pathological changes in the gray matter of the brain.

The cholinergic system in subtypes of Alzheimer's disease: an in vivo longitudinal MRI study.

BACKGROUND: The heterogeneity within Alzheimer's disease (AD) seriously challenges the development of disease-modifying treatments. We investigated volume of the basal forebrain, hippocampus, and precuneus in atrophy subtypes of AD and explored the relevance of subtype stratification in a small clinical trial on encapsulated cell biodelivery (ECB) of nerve growth factor (NGF) to the basal forebrain. METHODS: Structural MRI data was collected for 90 amyloid-positive patients and 69 amyloid-negative healthy controls at baseline, 6-, 12-, and 24-month follow-up. The effect of the NGF treatment was investigated in 10 biopsy-verified AD patients with structural MRI data at baseline and at 6- or 12-month follow-up. Patients were classified as typical, limbic-predominant, hippocampal-sparing, or minimal atrophy AD, using a validated visual assessment method. Volumetric analyses were performed using a region-of-interest approach. RESULTS: All AD subtypes showed reduced basal forebrain volume as compared with the healthy controls. The limbic-predominant subtype showed the fastest basal forebrain atrophy rate, whereas the minimal atrophy subtype did not show any significant volume decline over time. Atrophy rates of the hippocampus and precuneus also differed across subtypes. Our preliminary data from the small NGF cohort suggest that the NGF treatment seemed to slow the rate of atrophy in the precuneus and hippocampus in some hippocampal-sparing AD patients and in one typical AD patient. CONCLUSIONS: The cholinergic system is differentially affected in distinct atrophy subtypes of AD. Larger studies in the future should confirm that this differential involvement of the cholinergic system may contribute to subtype-specific response to cholinergic treatment. Our preliminary findings suggest that future clinical trials should target specific subtypes of AD, or at least report treatment effects stratified by subtype. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01163825. Registered 14 July 2010.