Chronic immunosuppression across 12 months and high ability of acute and subacute CNS-injury biomarker concentrations to identify individuals with complicated mTBI on acute CT and MRI.

BACKGROUND: Identifying individuals with intracranial injuries following mild traumatic brain injury (mTBI), i.e. complicated mTBI cases, is important for follow-up and prognostication. The main aims of our study were (1) to assess the temporal evolution of blood biomarkers of CNS injury and inflammation in individuals with complicated mTBI determined on computer tomography (CT) and magnetic resonance imaging (MRI); (2) to assess the corresponding discriminability of both single- and multi-biomarker panels, from acute to chronic phases after injury. METHODS: Patients with mTBI (n = 207), defined as Glasgow Coma Scale score between 13 and 15, loss of consciousness < 30 min and post-traumatic amnesia < 24 h, were included. Complicated mTBI - i.e., presence of any traumatic intracranial injury on neuroimaging - was present in 8% (n = 16) on CT (CT+) and 12% (n = 25) on MRI (MRI+). Blood biomarkers were sampled at four timepoints following injury: admission (within 72 h), 2 weeks (± 3 days), 3 months (± 2 weeks) and 12 months (± 1 month). CNS biomarkers included were glial fibrillary acidic protein (GFAP), neurofilament light (NFL) and tau, along with 12 inflammation markers. RESULTS: The most discriminative single biomarkers of traumatic intracranial injury were GFAP at admission (CT+: AUC = 0.78; MRI+: AUC = 0.82), and NFL at 2 weeks (CT+: AUC = 0.81; MRI+: AUC = 0.89) and 3 months (MRI+: AUC = 0.86). MIP-1ß and IP-10 concentrations were significantly lower across follow-up period in individuals who were CT+ and MRI+. Eotaxin and IL-9 were significantly lower in individuals who were MRI+ only. FGF-basic concentrations increased over time in MRI- individuals and were significantly higher than MRI+ individuals at 3 and 12 months. Multi-biomarker panels improved discriminability over single biomarkers at all timepoints (AUCs > 0.85 for admission and 2-week models classifying CT+ and AUC ≈ 0.90 for admission, 2-week and 3-month models classifying MRI+). CONCLUSIONS: The CNS biomarkers GFAP and NFL were useful single diagnostic biomarkers of complicated mTBI, especially in acute and subacute phases after mTBI. Several inflammation markers were suppressed in patients with complicated versus uncomplicated mTBI and remained so even after 12 months. Multi-biomarker panels improved diagnostic accuracy at all timepoints, though at acute and 2-week timepoints, the single biomarkers GFAP and NFL, respectively, displayed similar accuracy compared to multi-biomarker panels.

Poorer sleep health is associated with altered brain activation during cognitive control processing in healthy adults.

This study investigated how proactive and reactive cognitive control processing in the brain was associated with habitual sleep health. BOLD fMRI data were acquired from 81 healthy adults with normal sleep (41 females, age 20.96-39.58 years) during a test of cognitive control (Not-X-CPT). Sleep health was assessed in the week before MRI scanning, using both objective (actigraphy) and self-report measures. Multiple measures indicating poorer sleep health-including later/more variable sleep timing, later chronotype preference, more insomnia symptoms, and lower sleep efficiency-were associated with stronger and more widespread BOLD activations in fronto-parietal and subcortical brain regions during cognitive control processing (adjusted for age, sex, education, and fMRI task performance). Most associations were found for reactive cognitive control activation, indicating that poorer sleep health is linked to a "hyper-reactive" brain state. Analysis of time-on-task effects showed that, with longer time on task, poorer sleep health was predominantly associated with increased proactive cognitive control activation, indicating recruitment of additional neural resources over time. Finally, shorter objective sleep duration was associated with lower BOLD activation with time on task and poorer task performance. In conclusion, even in "normal sleepers," relatively poorer sleep health is associated with altered cognitive control processing, possibly reflecting compensatory mechanisms and/or inefficient neural processing.

Retirement age and disability status as pathways to later-life cognitive impairment: Evidence from the Norwegian HUNT Study linked with Norwegian population registers.

BACKGROUND: Research shows that retirement age is associated with later-life cognition but has not sufficiently distinguished between retirement pathways. We examined how retirement age was associated with later-life dementia and mild cognitive impairment (MCI) for people who retired via the disability pathway (received a disability pension prior to old-age pension eligibility) and those who retired via the standard pathway. METHODS: The study sample comprised 7210 participants from the Norwegian Trøndelag Health Study (HUNT4 70+, 2017-2019) who had worked for at least one year in 1967-2019, worked until age 55+, and retired before HUNT4. Dementia and MCI were clinically assessed in HUNT4 70+ when participants were aged 69-85 years. Historical data on participants' retirement age and pathway were retrieved from population registers. We used multinomial regression to assess the dementia/MCI risk for women and men retiring via the disability pathway, or early (<67 years), on-time (age 67, old-age pension eligibility) or late (age 68+) via the standard pathway. RESULTS: In our study sample, 9.5% had dementia, 35.3% had MCI, and 28.1% retired via the disability pathway. The disability retirement group had an elevated risk of dementia compared to the on-time standard retirement group (relative risk ratio [RRR]: 1.64, 95% CI 1.14-2.37 for women, 1.70, 95% CI 1.17-2.48 for men). MCI risk was lower among men who retired late versus on-time (RRR, 0.76, 95% CI 0.61-0.95). CONCLUSION: Disability retirees should be monitored more closely, and preventive policies should be considered to minimize the dementia risk observed among this group of retirees.

Longitudinal study of the effect of a 5-year exercise intervention on structural brain complexity in older adults. A Generation 100 substudy.

Physical inactivity has been identified as an important risk factor for dementia. High levels of cardiorespiratory fitness (CRF) have been shown to reduce the risk of dementia. However, the mechanism by which exercise affects brain health is still debated. Fractal dimension (FD) is an index that quantifies the structural complexity of the brain. The purpose of this study was to investigate the effects of a 5-year exercise intervention on the structural complexity of the brain, measured through the FD, in a subset of 105 healthy older adults participating in the randomized controlled trial Generation 100 Study. The subjects were randomized into control, moderate intensity continuous training, and high intensity interval training groups. Both brain MRI and CRF were acquired at baseline and at 1-, 3- and 5-years follow-ups. Cortical thickness and volume data were extracted with FreeSurfer, and FD of the cortical lobes, cerebral and cerebellar gray and white matter were computed. CRF was measured as peak oxygen uptake (VO2peak) using ergospirometry during graded maximal exercise testing. Linear mixed models were used to investigate exercise group differences and possible CRF effects on the brain's structural complexity. Associations between change over time in CRF and FD were performed if there was a significant association between CRF and FD. There were no effects of group membership on the structural complexity. However, we found a positive association between CRF and the cerebral gray matter FD (p < 0.001) and the temporal lobe gray matter FD (p < 0.001). This effect was not present for cortical thickness, suggesting that FD is a more sensitive index of structural changes. The change over time in CRF was associated with the change in temporal lobe gray matter FD from baseline to 5-year follow-up (p < 0.05). No association of the change was found between CRF and cerebral gray matter FD. These results demonstrated that entering old age with high and preserved CRF levels protected against loss of structural complexity in areas sensitive to aging and age-related pathology.

Normative data for pituitary size and volume in the general population between 50 and 66 years.

PURPOSE: The main aim of this study was to provide normative data for pituitary height and volume in persons between 50 and 66 years in the general population. The secondary aim was to establish a convenient surrogate marker of pituitary size for use in routine radiological practice. METHODS: From a geographically defined prospective healthy study, 1006 participants between 50 and 66 years had a brain MRI, of which 988 (519 women) were included in this study. We measured the mid-sagittal height, max-sagittal height and total volume of the anterior pituitary lobe based on T1-weighted 3D MRI images. RESULTS: Both the mean mid-sagittal and max-sagittal pituitary height were significantly larger in women compared to men, with 4.9 ± 1.7 mm versus 4.4 ± 1.4 mm (p < .001) for the mean mid-sagittal height and 6.8 ± 1.2 mm versus 6.1 ± 1.1 mm (p < 0.001) for the mean max-sagittal height. The mean anterior pituitary lobe volume was also significantly larger in women than in men (494 ± 138 mm3 vs. 405 ± 118 mm3) (p < 0.001). There were no significant differences in these pituitary sagittal heights nor volume in either sex between the age groups 50-54, 55-59 and 60-66 years. The 95th percentile for mid-sagittal height, max-sagittal height and pituitary volume was 7.7 mm, 8.6 mm and 851 mm3 for women and 6.6 mm, 7.8 mm and 610 mm3 for men. CONCLUSION: This study show that women have a larger pituitary gland than men in the age group between 50 and 66 years and provides normative data for pituitary size estimates which can be used for clinical diagnostic purposes as well as future research.

Diffusion kurtosis imaging in mild traumatic brain injury and postconcussional syndrome.

Aims of this study were to investigate white matter (WM) and thalamus microstructure 72 hr and 3 months after mild traumatic brain injury (TBI) with diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI), and to relate DKI and DTI findings to postconcussional syndrome (PCS). Twenty-five patients (72 hr = 24; 3 months = 23) and 22 healthy controls were recruited, and DKI and DTI data were analyzed with Tract-Based Spatial Statistics (TBSS) and a region-of-interest (ROI) approach. Patients were categorized into PCS or non-PCS 3 months after injury according to the ICD-10 research criteria for PCS. In TBSS analysis, significant differences between patients and controls were seen in WM, both in the acute stage and 3 months after injury. Fractional anisotropy (FA) reductions were more widespread than kurtosis fractional anisotropy (KFA) reductions in the acute stage, while KFA reductions were more widespread than the FA reductions at 3 months, indicating the complementary roles of DKI and DTI. When comparing patients with PCS (n = 9), without PCS (n = 16), and healthy controls, in the ROI analyses, no differences were found in the acute DKI and DTI metrics. However, near-significant differences were observed for several DKI metrics obtained in WM and thalamus concurrently with symptom assessment (3 months after injury). Our findings indicate a combined utility of DKI and DTI in detecting WM microstructural alterations after mild TBI. Moreover, PCS may be associated with evolving alterations in brain microstructure, and DKI may be a promising tool to detect such changes.

Neuroplasticity in stroke recovery. The role of microglia in engaging and modifying synapses and networks.

Neuroplasticity after ischaemic injury involves both spontaneous rewiring of neural networks and circuits as well as functional responses in neurogenic niches. These events involve complex interactions with activated microglia, which evolve in a dynamic manner over time. Although the exact mechanisms underlying these interactions remain poorly understood, increasing experimental evidence suggests a determining role of pro- and anti-inflammatory microglial activation profiles in shaping both synaptogenesis and neurogenesis. While the inflammatory response of microglia was thought to be detrimental, a more complex profile of the role of microglia in tissue remodelling is emerging. Experimental evidence suggests that microglia in response to injury can rapidly modify neuronal activity and modulate synaptic function, as well as be beneficial for the proliferation and integration of neural progenitor cells (NPCs) from endogenous neurogenic niches into functional networks thereby supporting stroke recovery. The manner in which microglia contribute towards sculpting neural synapses and networks, both in terms of activity-dependent and homeostatic plasticity, suggests that microglia-mediated pro- and/or anti-inflammatory activity may significantly contribute towards spontaneous neuronal plasticity after ischaemic lesions. In this review, we first introduce some of the key cellular and molecular mechanisms underlying neuroplasticity in stroke and then proceed to discuss the crosstalk between microglia and endogenous neuroplasticity in response to brain ischaemia with special focus on the engagement of synapses and neural networks and their implications for grey matter integrity and function in stroke repair.

White matter hyperintensities and headache: A population-based imaging study (HUNT MRI).

OBJECTIVE: To examine the relationship between white matter hyperintensities and headache. METHODS: White matter hyperintensities burden was assessed semi-quantitatively using Fazekas and Scheltens scales, and by manual and automated volumetry of MRI in a sub-study of the general population-based Nord-Trøndelag Health Study (HUNT MRI). Using validated questionnaires, participants were categorized into four cross-sectional headache groups: Headache-free (n = 551), tension-type headache (n = 94), migraine (n = 91), and unclassified headache (n = 126). Prospective questionnaire data was used to further categorize participants into groups according to the evolution of headache during the last 12 years: Stable headache-free, past headache, new onset headache, and persistent headache. White matter hyperintensities burden was compared across headache groups using adjusted multivariate regression models. RESULTS: Individuals with tension-type headache were more likely to have extensive white matter hyperintensities than headache-free subjects, with this being the case across all methods of white matter hyperintensities assessment (Scheltens scale: Odds ratio, 2.46; 95% CI, 1.44-4.20). Migraine or unclassified headache did not influence the odds of having extensive white matter hyperintensities. Those with new onset headache were more likely to have extensive white matter hyperintensities than those who were stable headache-free (Scheltens scale: Odds ratio, 2.24; 95% CI, 1.13-4.44). CONCLUSIONS: Having tension-type headache or developing headache in middle age was linked to extensive white matter hyperintensities. These results were similar across all methods of assessing white matter hyperintensities. If white matter hyperintensities treatment strategies emerge in the future, this association should be taken into consideration.

Effects of Neural Stem Cell and Olfactory Ensheathing Cell Co-transplants on Tissue Remodelling After Transient Focal Cerebral Ischemia in the Adult Rat.

Effective transplant-mediated repair of ischemic brain lesions entails extensive tissue remodeling, especially in the ischemic core. Neural stem cells (NSCs) are promising reparative candidates for stroke induced lesions, however, their survival and integration with the host-tissue post-transplantation is poor. In this study, we address this challenge by testing whether co-grafting of NSCs with olfactory ensheathing cells (OECs), a special type of glia with proven neuroprotective, immunomodulatory, and angiogenic effects, can promote graft survival and host tissue remodelling. Transient focal cerebral ischemia was induced in adult rats by a 60-min middle cerebral artery occlusion (MCAo) followed by reperfusion. Ischemic lesions were verified by neurological testing and magnetic resonance imaging. Transplantation into the globus pallidus of NSCs alone or in combination with OECs was performed at two weeks post-MCAo, followed by histological analyses at three weeks post-transplantation. We found evidence of extensive vascular remodelling in the ischemic core as well as evidence of NSC motility away from the graft and into the infarct border in severely lesioned animals co-grafted with OECs. These findings support a possible role of OECs as part of an in situ tissue engineering paradigm for transplant mediated repair of ischemic brain lesions.

A longitudinal study of associations between psychiatric symptoms and disorders and cerebral gray matter volumes in adolescents born very preterm.

BACKGROUND: Being born preterm with very low birthweight (VLBW ≤ 1500 g) poses a risk for cortical and subcortical gray matter (GM) abnormalities, as well as for having more psychiatric problems during childhood and adolescence than term-born individuals. The aim of this study was to investigate the relationship between cortical and subcortical GM volumes and the course of psychiatric disorders during adolescence in VLBW individuals. METHODS: We followed VLBW individuals and term-born controls (birth weight ≥10th percentile) from 15 (VLBW;controls n = 40;56) to 19 (n = 44;60) years of age. Of these, 30;37 individuals were examined longitudinally. Cortical and subcortical GM volumes were extracted from MRPRAGE images obtained with the same 1.5 T MRI scanner at both time points and analyzed at each time point with the longitudinal stream of the FreeSurfer software package 5.3.0. All participants underwent clinical interviews and were assessed for psychiatric symptoms and diagnosis (Schedule for Affective Disorders and Schizophrenia for School-age Children, Children's Global Assessment Scale, Attention-Deficit/Hyperactivity Disorder Rating Scale-IV). VLBW adolescents were divided into two groups according to diagnostic status from 15 to 19 years of age: persisting/developing psychiatric diagnosis or healthy/becoming healthy. RESULTS: Reduction in subcortical GM volume at 15 and 19 years, not including the thalamus, was limited to VLBW adolescents with persisting/developing diagnosis during adolescence, whereas VLBW adolescents in the healthy/becoming healthy group had similar subcortical GM volumes to controls. Moreover, across the entire VLBW group, poorer psychosocial functioning was predicted by smaller subcortical GM volumes at both time points and with reduced GM volume in the thalamus and the parietal and occipital cortex at 15 years. Inattention problems were predicted by smaller GM volumes in the parietal and occipital cortex. CONCLUSIONS: GM volume reductions in the parietal and occipital cortex as well as smaller thalamic and subcortical GM volumes were associated with the higher rates of psychiatric symptoms found across the entire VLBW group. Significantly smaller subcortical GM volumes in VLBW individuals compared with term-born peers might pose a risk for developing and maintaining psychiatric diagnoses during adolescence. Future research should explore the possible role of reduced cortical and subcortical GM volumes in the pathogenesis of psychiatric illness in VLBW adolescents.

Traumatic axonal injury: Relationships between lesions in the early phase and diffusion tensor imaging parameters in the chronic phase of traumatic brain injury.

This prospective study of traumatic brain injury (TBI) patients investigates fractional anisotropy (FA) from chronic diffusion tensor imaging (DTI) in areas corresponding to persistent and transient traumatic axonal injury (TAI) lesions detected in clinical MRI from the early phase. Thirty-eight patients (mean 24.7 [range 13-63] years of age) with moderate-to-severe TBI and 42 age- and sex-matched healthy controls were included. Patients underwent 1.5-T clinical MRI in the early phase (median 7 days), including fluid-attenuated inversion recovery (FLAIR) and T2* gradient echo (T2*GRE) sequences. TAI lesions from the early phase were characterized as nonhemorrhagic or microhemorrhagic. In the chronic phase (median 3 years), patients and controls were imaged at 3 T with FLAIR, T2*GRE, T1, and DTI sequences. TAI lesions were classified as transient or persistent. The FLAIR/T2*GRE images from the early phase were linearly registered to the FA images from the chronic phase and lesions manually segmented on the FA-registered FLAIR/T2*GRE images. For regions of interest (ROIs) from both nonhemorrhagic and microhemorrhagic lesion, we found a significant linear trend of lower mean FA from ROIs in healthy controls to ROIs in patients without either nonhemorrhagic or microhemorrhagic lesions and further to transient and finally persistent lesion ROIs (P < 0.001). Histogram analyses showed lower FA in persistent compared with transient nonhemorrhagic lesion ROIs (P < 0.001), but this was not found in microhemorrhagic lesion ROIs (P = 0.08-0.55). The demonstrated linear trend of lower FA values from healthy controls to persistent lesion ROIs was found in both nonhemorrhagic and microhemorrhagic lesions and indicates a gradual increasing disruption of the microstructure. Lower FA values in persistent compared with transient lesions were found only in nonhemorrhagic lesions. Thus, clinical MRI techniques are able to depict important aspects of white matter pathology across the stages of TBI. © 2016 Wiley Periodicals, Inc.

Altered Cognitive Control Activations after Moderate-to-Severe Traumatic Brain Injury and Their Relationship to Injury Severity and Everyday-Life Function.

This study investigated how the neuronal underpinnings of both adaptive and stable cognitive control processes are affected by traumatic brain injury (TBI). Functional magnetic resonance imaging (fMRI) was undertaken in 62 survivors of moderate-to-severe TBI (>1 year after injury) and 68 healthy controls during performance of a continuous performance test adapted for use in a mixed block- and event-related design. Survivors of TBI demonstrated increased reliance on adaptive task control processes within an a priori core region for cognitive control in the medial frontal cortex. TBI survivors also had increased activations related to time-on-task effects during stable task-set maintenance in right inferior parietal and prefrontal cortices. Increased brain activations in TBI survivors had a dose-dependent linear positive relationship to injury severity and were negatively correlated with self-reported cognitive control problems in everyday-life situations. Results were adjusted for age, education, and fMRI task performance. In conclusion, evidence was provided that the neural underpinnings of adaptive and stable control processes are differently affected by TBI. Moreover, it was demonstrated that increased brain activations typically observed in survivors of TBI might represent injury-specific compensatory adaptations also utilized in everyday-life situations.

Participation and engagement in online cognitive testing.

Web-based testing of cognitive abilities allows for large-scale assessments without geographical constraints. Yet, the extent to which it can reach populations beyond the typical demographic groups recruited for cognitive studies is unclear. This study focused on comparing the characteristics of individuals from a general population study (HUNT4) who chose to participate in a cognitive study (HUNT4-Hjernetrim) with those who did not. Additionally, we investigated participants' engagement and user experience. We obtained data on socio-demographics, health conditions (both physical and mental), self-reported cognitive or learning difficulties, and lifestyle factors of Hjernetrim participants and non-participants from the HUNT4 database. Hjernetrim involved 13 cognitive tests, administered through the online platform Memoro. We used logistic regressions to assess participation biases and linear regressions to assess participants' engagement and user experience. Of 65,851 HUNT4 participants invited via regular mail to Hjernetrim, 5634 (9.4%, aged 13-97, 54% women) participated. The best represented in the sample were 50-79-year-olds, women, tertiary educated, living alone, from urban areas, not occupationally active, and reporting memory complaints. Individuals who were aged 80+, had motor or vision impairments, and teenagers with learning disabilities, were underrepresented. Participants were more likely to have mental health problems, have or survived cancer and less likely to have cardiovascular disease. Participants logged on mainly during weekdays, the preferred time of day varied by age. On average, participants used 42 min and completed 78% of the tasks. Using PCs provided the most complete data. In terms of user experiences, 65% were positive while 14% were negative or reported technical difficulties. Overall, the study demonstrated that web-based methodology allowed for a relatively well-represented sample that included groups typically difficult to reach. The presence of somatic and mental diseases had a variable influence on participation. Participants finished most tests and reported positive experiences overall.

Longitudinal Associations Between Persistent Post-Concussion Symptoms and Blood Biomarkers of Inflammation and CNS-Injury After Mild Traumatic Brain Injury.

The aim of our study was to investigate the biological underpinnings of persistent post-concussion symptoms (PPCS) at 3 months following mild traumatic brain injury (mTBI). Patients (n = 192, age 16-60 years) with mTBI, defined as Glasgow Coma Scale (GCS) score between 13 and 15, loss of consciousness (LOC) <30 min, and post-traumatic amnesia (PTA) <24 h were included. Blood samples were collected at admission (within 72 h), 2 weeks, and 3 months. Concentrations of blood biomarkers associated with central nervous system (CNS) damage (glial fibrillary acidic protein [GFAP], neurofilament light [NFL], and tau) and inflammation (interferon gamma [IFNγ], interleukin [IL]-8, eotaxin, macrophage inflammatory protein-1-beta [MIP]-1ß, monocyte chemoattractant protein [MCP]-1, interferon-gamma-inducible protein [IP]-10, IL-17A, IL-9, tumor necrosis factor [TNF], basic fibroblast growth factor [FGF]-basic platelet-derived growth factor [PDGF], and IL-1 receptor antagonist [IL-1ra]) were obtained. Demographic and injury-related factors investigated were age, sex, GCS score, LOC, PTA duration, traumatic intracranial finding on magnetic resonance imaging (MRI; within 72 h), and extracranial injuries. Delta values, that is, time-point differences in biomarker concentrations between 2 weeks minus admission and 3 months minus admission, were also calculated. PPCS was assessed with the British Columbia Post-Concussion Symptom Inventory (BC-PSI). In single variable analyses, longer PTA duration and a higher proportion of intracranial findings on MRI were found in the PPCS group, but no single biomarker differentiated those with PPCS from those without. In multi-variable models, female sex, longer PTA duration, MRI findings, and lower GCS scores were associated with increased risk of PPCS. Inflammation markers, but not GFAP, NFL, or tau, were associated with PPCS. At admission, higher concentrations of IL-8 and IL-9 and lower concentrations of TNF, IL-17a, and MCP-1 were associated with greater likelihood of PPCS; at 2 weeks, higher IL-8 and lower IFNγ were associated with PPCS; at 3 months, higher PDGF was associated with PPCS. Higher delta values of PDGF, IL-17A, and FGF-basic at 2 weeks compared with admission, MCP-1 at 3 months compared with admission, and TNF at 2 weeks and 3 months compared with admission were associated with greater likelihood of PPCS. Higher IL-9 delta values at both time-point comparisons were negatively associated with PPCS. Discriminability of individual CNS-injury and inflammation biomarkers for PPCS was around chance level, whereas the optimal combination of biomarkers yielded areas under the curve (AUCs) between 0.62 and 0.73. We demonstrate a role of biological factors on PPCS, including both positive and negative effects of inflammation biomarkers that differed based on sampling time-point after mTBI. PPCS was associated more with acute inflammatory processes, rather than ongoing inflammation or CNS-injury biomarkers. However, the modest discriminative ability of the models suggests other factors are more important in the development of PPCS.

The functional topography and temporal dynamics of overlapping and distinct brain activations for adaptive task control and stable task-set maintenance during performance of an fMRI-adapted clinical continuous performance test.

Previous studies have demonstrated that stable and adaptive attention processes are mediated by partly overlapping, but distinct, brain areas. Dorsal medial PFC and anterior insula may form a "core network" for attention control, which is believed to operate on both temporal scales. However, both the existence of such a network as well as the unique functional topography for adaptive and stable attention processes is still highly debated. In this study, 87 healthy participants performed a clinical not-X continuous performance test optimized for use in a mixed block and event-related fMRI design. We observed overlapping activations related to stable and adaptive attention processes in dorsal medial PFC and anterior insula/adjacent cortex as well as in the right inferior parietal lobe and middle temporal gyrus. We also identified areas of activations uniquely related to stable and adaptive attention processes in widespread cortical, cerebellar, and subcortical areas. Interestingly, the functional topography within the PFC indicated a rostro-caudal distribution of adaptive, relative to stable, attention processes. There was also evidence for a time-on-task effect for activations related to stable, but not adaptive, attention processes. Our results provide further evidence for a "core network" for attention control that is accompanied by unique areas of activation involved in domain-specific processes operating on different temporal scales. In addition, our results give new insights into the functional topography of stable and adaptive attention processes and their temporal dynamics in the context of an extensively used clinical attention test.

Hippocampal neurochemicals are associated with exercise group and intensity, psychological health, and general cognition in older adults.

Based on the premise that physical activity/exercise impacts hippocampal structure and function, we investigated if hippocampal metabolites for neuronal viability and cell membrane density (i.e., N-acetyl aspartate (NAA), choline (Cho), creatine (Cr)) were higher in older adults performing supervised exercise compared to following national physical activity guidelines. Sixty-three participants (75.3 ± 1.9 years after 3 years of intervention) recruited from the Generation 100 study (NCT01666340_date:08.16.2012) were randomized into a supervised exercise group (SEG) performing twice weekly moderate- to high-intensity training, and a control group (CG) following national physical activity guidelines of ≥ 30-min moderate physical activity ≥ 5 days/week. Hippocampal body and head volumes and NAA, Cho, and Cr levels were acquired at 3T with magnetic resonance imaging and spectroscopic imaging. Sociodemographic data, peak oxygen uptake (VO2peak), exercise characteristics, psychological health, and cognition were recorded. General linear models were used to assess group differences and associations corrected for age, sex, education, and hippocampal volume. Both groups adhered to their training, where SEG trained at higher intensity. SEG had significantly lower NAA/Cr in hippocampal body than CG (p = 0.04). Across participants, higher training intensity was associated with lower Cho/Cr in hippocampal body (p < 0.001). Change in VO2peak, increasing VO2peak from baseline to 3 years, or VO2peak at 3 years were not associated with hippocampal neurochemicals. Lower NAA/Cr in hippocampal body was associated with poorer psychological health and slightly higher cognitive scores. Thus, following the national physical activity guidelines and not training at the highest intensity level were associated with the best neurochemical profile in the hippocampus at 3 years.

Trajectories of occupational physical activity and risk of later-life mild cognitive impairment and dementia: the HUNT4 70+ study.

Background: High levels of occupational physical activity (PA) have been linked to an increased risk of dementia. We assessed the association of trajectories of occupational PA at ages 33-65 with risk of dementia and mild cognitive impairment (MCI) at ages 70+. Methods: We included 7005 participants (49.8% were women, 3488/7005) from the HUNT4 70+ Study. Group-based trajectory modelling was used to identify four trajectories of occupational PA based on national registry data from 1960 to 2014: stable low (30.9%, 2162/7005), increasing then decreasing (8.9%, 625/7005), stable intermediate (25.1%, 1755/7005), and stable high (35.2%, 2463/7005). Dementia and MCI were clinically assessed in 2017-2019. We performed adjusted multinomial regression to estimate relative risk ratios (RRR) with 95% confidence intervals (CI) for dementia and MCI. Findings: 902 participants were diagnosed with dementia and 2407 were diagnosed with MCI. Absolute unadjusted risks for dementia and MCI were 8.8% (95% CI: 7.6-10.0) and 27.4% (25.5-29.3), respectively, for those with a stable low PA trajectory, 8.2% (6.0-10.4) and 33.3% (29.6-37.0) for those with increasing, then decreasing PA; while they were 16.0% (14.3-17.7) and 35% (32.8-37.2) for those with stable intermediate, and 15.4% (14.0-16.8) and 40.2% (38.3-42.1) for those with stable high PA trajectories. In the adjusted model, participants with a stable high trajectory had a higher risk of dementia (RRR 1.34, 1.04-1.73) and MCI (1.80, 1.54-2.11), whereas participants with a stable intermediate trajectory had a higher risk of MCI (1.36, 1.15-1.61) compared to the stable low trajectory. While not statistically significant, participants with increasing then decreasing occupational PA had a 24% lower risk of dementia and 18% higher risk of MCI than the stable low PA group. Interpretation: Consistently working in an occupation with intermediate or high occupational PA was linked to an increased risk of cognitive impairment, indicating the importance of developing strategies for individuals in physically demanding occupations to prevent cognitive impairment. Funding: This work was supported by the National Institutes of Health (R01AG069109-01) and the Research Council of Norway (296297, 262700, 288083).

Effects of 5 Years Aerobic Exercise on Cognition in Older Adults: The Generation 100 Study: A Randomized Controlled Trial.

OBJECTIVE: The objective of this study was to investigate whether a 5-year exercise intervention and change in peak oxygen uptake ([Formula: see text]) is associated with cognitive function in older adults. METHODS: Nine hundred and forty-five participants (48% women, mean age at study end 78.2 ± 2.02 years) from the Generation 100 Study were randomized 2:1:1 to a control group, moderate-intensity continuous training or high-intensity interval training twice weekly for 5 years. Peak oxygen uptake was measured using ergospirometry at baseline and after 5 years. Global cognition and mild cognitive impairment (MCI) were assessed with the Montreal Cognitive Assessment scale (MoCA) after 5 years. RESULTS: Compared to the control group, the combined moderate-intensity continuous training plus high-intensity interval training (ExComb) group did not have significantly different cognitive scores (beta value 0.26, 95% confidence interval [CI] - 0.17, 0.69) or odds of MCI (odds ratio 0.86, 95% CI 0.66, 1.13). Men in the ExComb group had 0.80 points higher MoCA (95% CI 0.21, 1.40) and 32% lower odds of MCI compared with male controls (95% CI 0.47, 0.99), with no such findings in women. In the total sample, each 1 metabolic equivalent of task increase in [Formula: see text] corresponded to 0.46 points higher MoCA (95% CI 0.25, 0.67) and 27% lower odds of MCI (95% CI 0.63, 0.85). Compared to [Formula: see text] stable, participants whose [Formula: see text] increased did not have significantly different cognitive scores (beta value 0.24, CI - 0.68, 1.15) or odds of MCI (odds ratio 0.70, 95% CI 0.36, 1.34), whereas participants whose [Formula: see text] decreased had 0.64 points lower MoCA (95% CI - 1.15, - 0.14) and 35% higher odds of MCI (95% CI 0.98, 1.87). CONCLUSIONS: Overall, exercise was not significantly associated with cognition among older adults. However, maintaining or increasing [Formula: see text] appeared to benefit cognition. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01666340.

Effects of a 5-Year Exercise Intervention on White Matter Microstructural Organization in Older Adults. A Generation 100 Substudy.

Aerobic fitness and exercise could preserve white matter (WM) integrity in older adults. This study investigated the effect on WM microstructural organization of 5 years of exercise intervention with either supervised moderate-intensity continuous training (MICT), high-intensity interval training (HIIT), or following the national physical activity guidelines. A total of 105 participants (70-77 years at baseline), participating in the randomized controlled trial Generation 100 Study, volunteered to take part in this longitudinal 3T magnetic resonance imaging (MRI) study. The HIIT group (n = 33) exercised for four intervals of 4 min at 90% of peak heart rate two times a week, the MICT group (n = 24) exercised continuously for 50 min at 70% peak heart rate two times a week, and the control group (n = 48) followed the national guidelines of ≥30 min of physical activity almost every day. At baseline and at 1-, 3-, and 5-year follow-ups, diffusion tensor imaging (DTI) scans were performed, cardiorespiratory fitness (CRF) was measured as peak oxygen uptake (VO2peak) with ergospirometry, and information on exercise habits was collected. There was no group*time or group effect on any of the DTI indices at any time point during the intervention. Across all groups, CRF was positively associated with fractional anisotropy (FA) and axial diffusivity (AxD) at the follow-ups, and the effect became smaller with time. Exercise intensity was associated with mean diffusivity (MD)/FA, with the greatest effect at 1-year and no effect at 5-year follow-up. There was an association between exercise duration and FA and radial diffusivity (RD) only after 1 year. Despite the lack of group*time interaction or group effect, both higher CRF and exercise intensity was associated with better WM microstructural organization throughout the intervention, but the effect became attenuated over time. Different aspects of exercising affected the WM metrics and WM tracts differently with the greatest and most overlapping effects in the corpus callosum. The current study indicates not only that high CRF and exercise intensity are associated with WM microstructural organization in aging but also that exercise's positive effects on WM may decline with increasing age.

One-Year Prospective Study of Plasma Biomarkers From CNS in Patients With Mild Traumatic Brain Injury.

Objective: To investigate the longitudinal evolution of three blood biomarkers: neurofilament light (NFL), glial fibrillary acidic protein (GFAP) and tau, in out-patients and hospitalized patients with mild traumatic brain injury (mTBI) compared to controls, along with their associations-in patients-with clinical injury characteristics and demographic variables, and ability to discriminate patients with mTBI from controls. Methods: A longitudinal observation study including 207 patients with mTBI, 84 age and sex-matched community controls (CCs) and 52 trauma controls (TCs). Blood samples were collected at 5 timepoints: acute (<24 h), 72 h (24-72 h post-injury), 2 weeks, 3 and 12 months. Injury-related, clinical and demographic variables were obtained at inclusion and brain MRI within 72 h. Results: Plasma GFAP and tau were most elevated acutely and NFL at 2 weeks and 3 months. The group of patients with mTBI and concurrent other somatic injuries (mTBI+) had the highest elevation in all biomarkers across time points, and were more likely to be victims of traffic accidents and violence. All biomarkers were positively associated with traumatic intracranial findings on MRI obtained within 72 h. Glial fibrillary acidic protein and NFL levels were associated with Glasgow Coma Scale (GCS) score and presence of other somatic injuries. Acute GFAP concentrations showed the highest discriminability between patients and controls with an Area Under the Curve (AUC) of 0.92. Acute tau and 2-week NFL concentrations showed moderate discriminability (AUC = 0.70 and AUC = 0.75, respectively). Tau showed high discriminability between mTBI+ and TCs (AUC = 0.80). Conclusions: The association of plasma NFL with traumatic intracranial MRI findings, together with its later peak, could reflect ongoing secondary injury or repair mechanisms, allowing for a protracted diagnostic time window. Patients experiencing both mTBI and other injuries appear to be a subgroup with greater neural injury, differing from both the mTBI without other injuries and from both control groups. Acute GFAP concentrations showed the highest discriminability between patients and controls, were highly associated with intracranial traumatic injury, and showed the largest elevations compared to controls at the acute timepoint, suggesting it to be the most clinically useful plasma biomarker of primary CNS injury in mTBI.