Blood pressure trajectories over 35 years and dementia risk: A retrospective study: The HUNT study

High blood pressure is a well-established risk factor of dementia. However, the timing of the risk remains controversial. The aim of the present study was to compare trajectories of systolic blood pressure (SBP) over a 35-year follow-up period in the Health Survey in Trøndelag (HUNT) from study wave 1 to 4 in people with and without a dementia diagnosis at wave 4 (HUNT4). This is a retrospective cohort study of participants aged ≥ 70 years in HUNT4, where 9,720 participants were assessed for dementia. In the HUNT study all residents aged ≥ 20 years have been invited to four surveys: HUNT1 1984–86, HUNT2 1995–97, HUNT3 2006–08 and HUNT4 2017–19. The study sample was aged 70–102 years (mean 77.6, SD 6.0) at HUNT4, 54% were women and 15.5% had dementia, 8.8% had Alzheimer’s disease (AD), 1.6% had vascular dementia (VaD) and 5.1% had other types of dementia. Compared to those without dementia at HUNT4, those with dementia at HUNT4 had higher SBP at HUNT1 and HUNT2, but lower SBP at HUNT4. These differences at HUNT1 and 2 were especially pronounced among women. Results did not differ across birth cohorts. For dementia subtypes at HUNT4, the VaD group had a higher SBP than the AD group at HUNT2 and 3. Age trajectories in SBP showed that the dementia group experienced a steady increase in SBP until 65 years of age and a decrease from 70 to 90 years. SBP in the no- dementia group increased until 80 years before it leveled off from 80 to 90 years. The present study confirms findings of higher midlife SBP and lower late-life SBP in people with dementia. This pattern may have several explanations and it highlights the need for close monitoring of BP treatment in older adults, with frequent reappraisal of treatment needs

Blood pressure trajectories over 35 years and dementia risk: A retrospective study: The HUNT study

High blood pressure is a well-established risk factor of dementia. However, the timing of the risk remains controversial. The aim of the present study was to compare trajectories of systolic blood pressure (SBP) over a 35-year follow-up period in the Health Survey in Trøndelag (HUNT) from study wave 1 to 4 in people with and without a dementia diagnosis at wave 4 (HUNT4). This is a retrospective cohort study of participants aged ≥ 70 years in HUNT4, where 9,720 participants were assessed for dementia. In the HUNT study all residents aged ≥ 20 years have been invited to four surveys: HUNT1 1984–86, HUNT2 1995–97, HUNT3 2006–08 and HUNT4 2017–19. The study sample was aged 70–102 years (mean 77.6, SD 6.0) at HUNT4, 54% were women and 15.5% had dementia, 8.8% had Alzheimer’s disease (AD), 1.6% had vascular dementia (VaD) and 5.1% had other types of dementia. Compared to those without dementia at HUNT4, those with dementia at HUNT4 had higher SBP at HUNT1 and HUNT2, but lower SBP at HUNT4. These differences at HUNT1 and 2 were especially pronounced among women. Results did not differ across birth cohorts. For dementia subtypes at HUNT4, the VaD group had a higher SBP than the AD group at HUNT2 and 3. Age trajectories in SBP showed that the dementia group experienced a steady increase in SBP until 65 years of age and a decrease from 70 to 90 years. SBP in the no- dementia group increased until 80 years before it leveled off from 80 to 90 years. Frontiers in Aging Neuroscience. The present study confirms findings of higher midlife SBP and lower late-life SBP in people with dementia. This pattern may have several explanations and it highlights the need for close monitoring of BP treatment in older adults, with frequent reappraisal of treatment needs.publishedVersio

Mapping trends in the care workforce using SOC 1990 and SOC 2000

NAT12/NAA30 knockdown resulted in dysregulation of the hypoxia response pathway as shown by microarray analysis. Asterisks signify p values and indicate level of significance. *=(p≈0.01-0.05), **=(p≈0.001-0.01)

Temporal changes in personal activity intelligence and the risk of incident dementia and dementia related mortality: A prospective cohort study (HUNT)

Background: The Personal Activity Intelligence (PAI) translates heart rate during daily activity into a weekly score. Obtaining a weekly PAI score ≥100 is associated with reduced risk of premature morbidity and mortality from cardiovascular diseases. Here, we determined whether changes in PAI score are associated with changes in risk of incident dementia and dementia-related mortality. Methods: We conducted a prospective cohort study of 29,826 healthy individuals. Using data from the Trøndelag Health-Study (HUNT), PAI was estimated 10 years apart (HUNT1 1984-86 and HUNT2 1995-97). Adjusted hazard-ratios (aHR) and 95%-confidence intervals (CI) for incidence of and death from dementia were related to changes in PAI using Cox regression analyses. Findings: During a median follow-up time of 24.5 years (interquartile range [IQR]: 24.1-25.0) for dementia incidence and 23.6 years (IQR: 20.8-24.2) for dementia-related mortality, there were 1998 incident cases and 1033 dementia-related deaths. Individuals who increased their PAI score over time or maintained a high PAI score at both assessments had reduced risk of dementia incidence and dementia-related mortality. Compared with persistently inactive individuals (0 weekly PAI) at both time points, the aHRs for those with a PAI score ≥100 at both occasions were 0.75 (95% CI: 0.58-0.97) for incident dementia, and 0.62 (95% CI: 0.43-0.91) for dementia-related mortality. Using PAI score <100 at both assessments as the reference cohort, those who increased from <100 at HUNT1 to ≥100 at HUNT2 had aHR of 0.83 (95% CI: 0.72-0.96) for incident dementia, and gained 2.8 (95% CI: 1.3-4.2, P<0.0001) dementia-free years. For dementia-related mortality, the corresponding aHR was 0.74 (95% CI: 0.59-0.92) and years of life gained were 2.4 (95% CI: 1.0-3.8, P=0.001). Interpretation: Maintaining a high weekly PAI score and increases in PAI scores over time were associated with a reduced risk of incident dementia and dementia-related mortality. Our findings extend the scientific evidence regarding the protective role of PA for dementia prevention, and suggest that PAI may be a valuable tool in guiding research-based PA recommendations. Funding: The Norwegian Research Council, the Liaison Committee between the Central Norway Regional Health Authority and Norwegian University of Science and Technology (NTNU), Trondheim, Norway.The Norwegian Research Council, the Liaison Committee between the Central Norway Regional Health Authority and Norwegian University of Science and Technology (NTNU), Trondheim, Norway.publishedVersio

Acute energy deprivation in isolated neurons and tumor stem cells. Effects on intracellular calcium and mitochondrial function

Acute brain hypoxia/ischemia can occur in all parts of life e.g. during birth, trauma or disease, of which stroke is the most common cause. Neuroprotective measures are yet sparse. Tolerance to energy deprivation due to hypoxia or ischemia would be of great value in the acutely diseased brain. Such tolerance is limited in the adult human brain, which is the usual victim of stroke. Conversely in neonatal individuals such tolerance has been seen, as well as in malignant tissue where hypoxia tolerance is associated with therapy resistance. Loss of cellular calcium homeostasis and mitochondrial depolarization are key events leading to cell death. The aim of this thesis was to investigate the state of intracellular calcium and mitochondrial function after the onset of acute ischemia/hypoxia in neurons of the neonate and adult brain, and in patient-derived glioblastoma stem cells (GSCs) and their differentiated progeny. The results suggest that the sarcoplasmic/endoplasmic calcium ATPase (SERCA) is important in ischemic calcium deregulation. In addition, hypoxia was more deleterious to mitochondria than glutamate overload and glucose deprivation. Mitochondrial function was better preserved in neonatal neurons than in adults when exposed to acute hypoxia and reoxygenation. GSCs were surprisingly sensitive to hypoxia. However, short-term differentiation improved hypoxia tolerance. In conclusion oxygen dependency changes with development both in neurons and in tumor stem cells. Acquired hypoxia tolerance during stimulated differentiation in GSCs demonstrates a plasticity that brings hope to the idea of inducing hypoxia tolerance in the human brain

Prescription of potentially addictive medications after a multilevel community intervention in general practice

AbstractObjective To evaluate the long-term effects of a multilevel community intervention to improve the quality of prescription practice of potentially addictive medications (PAMs).Design We conducted a retrospective study, using anonymized data from the Norwegian prescription registry.Setting Based on an initiative from the GPs in Molde Municipality in Norway, a multilevel community intervention was initiated by the municipal chief physician in 2018. The intervention targeted GPs, patients, and the public.Subjects We retrieved prescription data from 26 of 36 GPs.Main outcome measures By using the standardized defined daily dose (DDD), we compared prescription of three groups of PAMs from before the intervention (2017) throughout the intervention in 2018, and through 2020 to determine long-term effects.Results Three years after the intervention, the GPs in our study sample prescribed 26% less opioids, 38% less benzodiazepines, and 16% less z-hypnotics. Overall prescription of PAMs decreased by 27%. The number of individuals receiving at least 90 DDD of benzodiazepines and z-hypnotics were reduced from 9 to 7 and 34 to 24 per 1000, respectively. Also, the number of individuals receiving two and three PAMs concomitantly were reduced.Conclusion Addressing prescription practice among GPs in a community as a joint intervention, combined with addressing patients and the public may be a feasible method to obtain long-term reduction of PAM prescriptions.Key pointsNon-therapeutic prescriptions of potentially addictive medications (PAMs) are both a public health concern and a frequent challenge in general practice.A multilevel community intervention, targeting general practitioners, patients, and the public, led to 27% reduction in prescription of PAMs.Both the number of daily users and concomitant use of several PAMs were reduced.The reduction in prescription persisted for three years

Knockdown of NAT12/NAA30 reduces tumorigenic features of glioblastoma-initiating cells

Background Glioblastoma (GBM) is the most common primary brain malignancy and confers a dismal prognosis. GBMs harbor glioblastoma-initiating cells (GICs) that drive tumorigenesis and contribute to therapeutic resistance and tumor recurrence. Consequently, there is a strong rationale to target this cell population in order to develop new molecular therapies against GBM. Accumulating evidence indicates that Nα-terminal acetyltransferases (NATs), that are dysregulated in numerous human cancers, can serve as therapeutic targets. Methods Microarrays were used to study the expression of several NATs including NAT12/NAA30 in clinical samples and stem cell cultures. The expression of NAT12/NAA30 was analyzed using qPCR, immunolabeling and western blot. We conducted shRNA-mediated knockdown of NAT12/NAA30 gene in GICs and studied the effects on cell viability, sphere-formation and hypoxia sensitivity. Intracranial transplantation to SCID mice enabled us to investigate the effects of NAT12/NAA30 depletion in vivo. Using microarrays we identified genes and biochemical pathways whose expression was altered upon NAT12/NAA30 down-regulation. Results While decreased expression of the distal 3’UTR of NAT12/NAA30 was generally observed in GICs and GBMs, this gene was strongly up-regulated at the protein level in GBM and GICs. The increased protein levels were not caused by increased levels of the steady state mRNA but rather by other mechanisms. Also, shorter 3’UTR of NAT12/NAA30 correlated with poor survival in glioma patients. As well, we observed previously not described nuclear localization of this typically cytoplasmic protein. When compared to non-silencing controls, cells featuring NAT12/NAA30 knockdown exhibited reduced cell viability, sphere-forming ability, and mitochondrial hypoxia tolerance. Intracranial transplantation showed that knockdown of NAT12/NAA30 resulted in prolonged animal survival. Microarray analysis of the knockdown cultures showed reduced levels of HIF1α and altered expression of several other genes involved in the hypoxia response. Furthermore, NAT12/NAA30 knockdown correlated with expressional dysregulation of genes involved in the p53 pathway, ribosomal assembly and cell proliferation. Western blot analysis revealed reduction of HIF1α, phospho-MTOR(Ser2448) and higher levels of p53 and GFAP in these cultures. Conclusion NAT12/NAA30 plays an important role in growth and survival of GICs possibly by regulating hypoxia response (HIF1α), levels of p-MTOR (Ser2448) and the p53 pathway

Physical performance across the cognitive spectrum and between dementia subtypes in a population-based sample of older adults: The HUNT study

Background: Literature on physical performance in older adults across the cognitive spectrum remains inconclusive, and knowledge on differences between dementia subtypes is lacking. We aim to identify distinct physical-performance deficits across the cognitive spectrum and between dementia subtypes. Methods: 11,466 persons were included from the 70-year-and-older cohort in the fourth wave of the Trøndelag Health Study (HUNT4 70+). Physical performance was assessed with the Short Physical Performance Battery (SPPB), 4-meter gait speed, five-times-sit-to-stand (FTSS), grip strength and one-leg-standing (OLS). Clinical experts diagnosed dementia per DSM-5 criteria. Multiple linear and logistic regression were performed to analyze differences between groups. Age, sex, education, somatic comorbidity, physical activity and smoking status were used as covariates. Results: Gait speed declined across the cognitive spectrum, beginning in people with subjective cognitive decline (SCD). Participants with mild cognitive impairment (MCI) additionally showed reduced lower-limb muscle strength, balance and grip strength. Those with dementia scored lowest on all physical-performance measures. Participants with Alzheimer's disease (AD) had a higher SPPB sum score and faster gait speed than participants with vascular dementia (VaD) and Lewy body dementia (LBD); participants with VaD and LBD had lower odds of being able to perform FTSS and OLS than participants with AD. Conclusions: Physical performance declined across the spectrum from cognitively healthy to SCD to MCI and to dementia. Participants with AD performed better on all assessments except grip strength than participants with VaD and LBD. Stage of cognitive impairment and dementia subtype should guide exercise interventions to prevent mobility decline and dependency

Blood pressure trajectories over 35 years and dementia risk: A retrospective study: The HUNT study

High blood pressure is a well-established risk factor of dementia. However, the timing of the risk remains controversial. The aim of the present study was to compare trajectories of systolic blood pressure (SBP) over a 35-year follow-up period in the Health Survey in Trøndelag (HUNT) from study wave 1 to 4 in people with and without a dementia diagnosis at wave 4 (HUNT4). This is a retrospective cohort study of participants aged ≥ 70 years in HUNT4, where 9,720 participants were assessed for dementia. In the HUNT study all residents aged ≥ 20 years have been invited to four surveys: HUNT1 1984-86, HUNT2 1995-97, HUNT3 2006-08 and HUNT4 2017-19. The study sample was aged 70-102 years (mean 77.6, SD 6.0) at HUNT4, 54% were women and 15.5% had dementia, 8.8% had Alzheimer's disease (AD), 1.6% had vascular dementia (VaD) and 5.1% had other types of dementia. Compared to those without dementia at HUNT4, those with dementia at HUNT4 had higher SBP at HUNT1 and HUNT2, but lower SBP at HUNT4. These differences at HUNT1 and 2 were especially pronounced among women. Results did not differ across birth cohorts. For dementia subtypes at HUNT4, the VaD group had a higher SBP than the AD group at HUNT2 and 3. Age trajectories in SBP showed that the dementia group experienced a steady increase in SBP until 65 years of age and a decrease from 70 to 90 years. SBP in the no- dementia group increased until 80 years before it leveled off from 80 to 90 years. The present study confirms findings of higher midlife SBP and lower late-life SBP in people with dementia. This pattern may have several explanations and it highlights the need for close monitoring of BP treatment in older adults, with frequent reappraisal of treatment needs.Helse Sør-Øst: 251687publishedVersio

Temporal changes in cardiorespiratory fitness and risk of dementia incidence and mortality: a population-based prospective cohort study

Cardiorespiratory fitness is associated with risk of dementia, but whether temporal changes in cardiorespiratory fitness influence the risk of dementia incidence and mortality is still unknown. We aimed to study whether change in estimated cardiorespiratory fitness over time is associated with change in risk of incident dementia, dementia-related mortality, time of onset dementia, and longevity after diagnosis in healthy men and women at baseline. Methods We linked data from the prospective Nord-Trøndelag Health Study (HUNT) done in Nord-Trøndelag, Norway with dementia data from the Health and Memory Study and cause of death registries (n=30 375). Included participants were apparently healthy individuals for whom data were available on estimated cardiorespiratory fitness and important confounding factors. Datasets were matched to each participant through their 11-digit personal identification number. Cardiorespiratory fitness was estimated on two occasions 10 years apart, during HUNT1 (1984–86) and HUNT2 (1995–97). HUNT2 was used as the baseline for follow-up. Participants were classified into two sex-specific estimated cardiorespiratory fitness groups according to their age (10-year categories): unfit (least fit 20% of participants) and fit (most fit 80% of participants). To assess the association between change in estimated cardiorespiratory fitness and dementia, we used four categories of change: unfit at both HUNT1 and HUNT2, unfit at HUNT1 and fit at HUNT2, fit at HUNT1 and unfit at HUNT2, fit at both HUNT1 and HUNT2. Using Cox proportional hazard analyses, we estimated adjusted hazard ratios (AHR) for dementia incidence and mortality related to temporal changes in estimated cardiorespiratory fitness. Findings During a median follow-up of 19·6 years for mortality, and 7·6 years for incidence, there were 814 dementia-related deaths, and 320 incident dementia cases. Compared with participants who were unfit at both assessments, participants who sustained high estimated cardiorespiratory fitness had a reduced risk of incident dementia (AHR 0·60, 95% CI 0·36–0·99) and a reduced risk of dementia mortality (0·56, 0·43–0·75). Participants who had an increased estimated cardiorespiratory fitness over time had a reduced risk of incident dementia (AHR 0·52, 95% CI 0·30–0·90) and dementia mortality (0·72, 0·52–0·99) when compared with those who remained unfit at both assessments. Each metabolic equivalent of task increase in estimated cardiorespiratory fitness was associated with a risk reduction of incident dementia (adjusted HR 0·84, 95% CI 0·75–0·93) and dementia mortality (0·90, 0·84–0·97). Participants who increased their estimated cardiorespiratory fitness over time gained 2·2 (95% CI 1·0–3·5) dementia-free years, and 2·7 (0·4–5·8) years of life when compared with those who remained unfit at both assessments. Interpretation Change in estimated cardiorespiratory fitness is an independent risk factor for incidence dementia and dementia mortality. Maintaining or improving cardiorespiratory fitness over time may be a target to reduce risk of dementia incidence and mortality, delay onset, and increase longevity after diagnosis. Our data highlight the importance of assessing cardiorespiratory fitness in health risk assessment for people at risk of dementia