Both brain size and biological sex contribute to variation in white matter microstructure in middle-aged healthy adults

Whether head size and/or biological sex influence proxies of white matter (WM) microstructure such as fractional anisotropy (FA) and mean diffusivity (MD) remains controversial. Diffusion tensor imaging (DTI) indices are also associated with age, but there are large discrepancies in the spatial distribution and timeline of age-related differences reported. The aim of this study was to evaluate the associations between intracranial volume (ICV), sex, and age and DTI indices from WM in a population-based study of healthy individuals (n = 812) aged 50–66 in the Nord-Trøndelag health survey. Semiautomated tractography and tract-based spatial statistics (TBSS) analyses were performed on the entire sample and in an ICV-matched sample of men and women. The tractography results showed a similar positive association between ICV and FA in all major WM tracts in men and women. Associations between ICV and MD, radial diffusivity and axial diffusivity were also found, but to a lesser extent than FA. The TBSS results showed that both men and women had areas of higher and lower FA when controlling for age, but after controlling for age and ICV only women had areas with higher FA. The ICV matched analysis also demonstrated that only women had areas of higher FA. Age was negatively associated with FA across the entire WM skeleton in the TBSS analysis, independent of both sex and ICV. Combined, these findings demonstrated that both ICV and sex contributed to variation in DTI indices and emphasized the importance of considering ICV as a covariate in DTI analysis

Prevalence of intracranial artery stenosis in a general population using 3D-time of flight magnetic resonance angiography

Background: Data on prevalence of intracranial artery stenosis (ICAS) in Western populations is sparse. The aim of the study was to assess the prevalence and risk factors for ICAS in a mainly Caucasian general population. Methods: We assessed the prevalence of ICAS in 1847 men and women aged 40 to 84 years who participated in a cross-sectional population-based study, using 3-dimensional time-of-flight 3 Tesla magnetic resonance angiography. ICAS was defined as a focal luminal flow diameter reduction of ≥50 %. The association between cardiovascular risk factor levels and ICAS was assessed by multivariable regression analysis. Results: The overall prevalence of ICAS was 6.0 % (95 % confidence interval (CI) 5.0–7.2), 4.3 % (95 % CI 3.1–5.7) in women and 8.0 % (95 % CI 6.3–10.0) in men. The prevalence increased by age from 0.8 % in 40-54 years age group to 15.2 % in the 75-84 years age group. The majority of stenoses was located to the internal carotid artery (52.2 %), followed by the posterior circulation (33.1 %), the middle cerebral artery (10.8 %) and the anterior cerebral artery (3.8 %). The risk of ICAS was independently associated with higher age, male sex, hypertension, hyperlipidemia, diabetes mellitus, current smoking and higher BMI. Conclusions: The prevalence of ICAS in a general population of Caucasians was relatively high and similar to the prevalence of extracranial internal carotid artery stenosis in previous population-based studies

What does hand motor function tell us about our aging brain in association with WMH?

Background - White matter hyperintensities (WMH) are a common cerebral finding in older people. WMH are usually asymptomatic, but excessive WMH are associated with cognitive decline and dementia. WMH are also among the neurological findings most consistently associated with declining motor performance in healthy ageing. Aims - To determine if WMH load is associated with simple and complex motor movements in dominant and non-dominant hands in cognitively intact older subjects. Methods - Hand motor performance was assessed with the Purdue Pegboard and Finger-tapping tests on 44 healthy right-handed participants, mean age 70.9 years (range 59–84 years). Participants also underwent magnetic resonance (MR) imaging, which were used to quantify WMH volume. The effect of WMH on the motor parameters was assessed via mediation analyses. Results - WMH load increased significantly with age, while the motor scores decreased significantly with age. WMH load mediated only the relationship between age and left-hand pegboard scores. Discussion - WMH mediated only the more complex Purdue Pegboard task for the non-dominant hand. This is likely because complex movements in the non-dominant hand recruit a larger cerebral network, which is more vulnerable to WMH. Conclusions - Complex hand movements in the non-dominant hand are mediated by WMH. Subtle loss of motor movements of non-dominant hand might predict future excessive white matter atrophy

Prevalence of unruptured intracranial aneurysms: impact of different definitions-the Tromsø Study

Background - Management of incidental unruptured intracranial aneurysms (UIAs) remains challenging and depends on their risk of rupture, estimated from the assumed prevalence of aneurysms and the incidence of aneurysmal subarachnoid haemorrhage. Reported prevalence varies, and consistent criteria for definition of UIAs are lacking. We aimed to study the prevalence of UIAs in a general population according to different definitions of aneurysm. Methods - Cross-sectional population-based study using 3-dimensional time-of-flight 3 Tesla MR angiography to identify size, type and location of UIAs in 1862 adults aged 40–84 years. Size was measured as the maximal distance between any two points in the aneurysm sac. Prevalence was estimated for different diameter cutoffs (≥1, 2 and 3 mm) with and without inclusion of extradural aneurysms. Results - The overall prevalence of intradural saccular aneurysms ≥2 mm was 6.6% (95% CI 5.4% to 7.6%), 7.5% (95% CI 5.9% to 9.2%) in women and 5.5% (95% CI 4.1% to 7.2%) in men. Depending on the definition of an aneurysm, the overall prevalence ranged from 3.8% (95% CI 3.0% to 4.8%) for intradural aneurysms ≥3 mm to 8.3% (95% CI 7.1% to 9.7%) when both intradural and extradural aneurysms ≥1 mm were included. Conclusion - Prevalence in this study was higher than previously observed in other Western populations and was substantially influenced by definitions according to size and extradural or intradural location. The high prevalence of UIAs sized <5 mm may suggest lower rupture risk than previously estimated. Consensus on more robust and consistent radiological definitions of UIAs is warranted

The antidepressant effect of intermittent theta burst stimulation (iTBS): study protocol for a randomized double-blind sham-controlled trial

Background Intermittent theta burst stimulation (iTBS) when applied over the left dorsolateral prefrontal cortex (DLPFC) has been shown to be equally effective and safe to treat depression compared to traditional repetitive transcranial magnetic stimulation (rTMS) paradigms. This protocol describes a funded single-centre, double-blind, randomized placebo-controlled, clinical trial to investigate the antidepressive effects of iTBS and factors associated with an antidepressive response. Methods In this trial, outpatients (N=96, aged 22–65 years) meeting the diagnostic criteria for at least moderate depression (Montgomery and Aasberg Depression Rating Scale score≥20) will be enrolled prospectively and receive ten, once-a-day sessions of either active iTBS or sham iTBS to the left DLPFC, localized via a neuronavigation system. Participants may have any degree of treatment resistance. Prior to stimulation, participants will undergo a thorough safety screening and a brief diagnostic assessment, genetic analysis of brain-derived neurotropic factor, 5-HTTLPR and 5-HT1A, and cerebral MRI assessments. A selection of neuropsychological tests and questionnaires will be administered prior to stimulation and after ten stimulations. An additional follow-up will be conducted 4 weeks after the last stimulation. The frst participant was enrolled on June 4, 2022. Study completion will be in December 2027. The project is approved by the Regional Ethical Committee of Medicine and Health Sciences, Northern Norway, project number 228765. The trial will be conducted according to Good Clinical Practice and published safety guidelines on rTMS treatment. Discussion The aims of the present trial are to investigate the antidepressive effect of a 10-session iTBS protocol on moderately depressed outpatients and to explore the factors that can explain the reduction in depressive symptoms after iTBS but also a poorer response to the treatment. In separate, but related work packages, the trial will assess how clinical, cognitive, brain imaging and genetic measures at baseline relate to the variability in the antidepressive effects of iTBS

The effect of white matter hyperintensities on regional brain volumes and white matter microstructure, a population-based study in HUNT

Even though age-related white matter hyperintensities (WMH) begin to emerge in middle age, their effect on brain micro- and macrostructure in this age group is not fully elucidated. We have examined how presence of WMH and load of WMH affect regional brain volumes and microstructure in a validated, representative general population sample of 873 individuals between 50 and 66 years. Presence of WMH was determined as Fazakas grade ≥1. WMH load was WMH volume from manual tracing of WMHs divided on intracranial volume. The impact of age appropriate WMH (Fazakas grade 1) on the brain was also investigated. Major novel findings were that even the age appropriate WMH group had widespread macro- and microstructural changes in gray and white matter, showing that the mere presence of WMH, not just WMH load is an important clinical indicator of brain health. With increasing WMH load, structural changes spread centrifugally. Further, we found three major patterns of FA and MD changes related to increasing WMH load, demonstrating a heterogeneous effect on white matter microstructure, where distinct patterns were found in the proximity of the lesions, in deep white matter and in white matter near the cortex. This study also raises several questions about the onset of WMH related pathology, in particular, whether some of the aberrant brain structural and microstructural findings are present before the emergence of WMH. We also found, similar to other studies, that WMH risk factors had low explanatory power for WMH, making it unclear which factors lead to WMH

The effect of white matter hyperintensities on regional brain volumes and white matter microstructure, a population-based study in HUNT

Even though age-related white matter hyperintensities (WMH) begin to emerge in middle age, their effect on brain micro- and macrostructure in this age group is not fully elucidated. We have examined how presence of WMH and load of WMH affect regional brain volumes and microstructure in a validated, representative general population sample of 873 individuals between 50 and 66 years. Presence of WMH was determined as Fazakas grade ≥1. WMH load was WMH volume from manual tracing of WMHs divided on intracranial volume. The impact of age appropriate WMH (Fazakas grade 1) on the brain was also investigated. Major novel findings were that even the age appropriate WMH group had widespread macro- and microstructural changes in gray and white matter, showing that the mere presence of WMH, not just WMH load is an important clinical indicator of brain health. With increasing WMH load, structural changes spread centrifugally. Further, we found three major patterns of FA and MD changes related to increasing WMH load, demonstrating a heterogeneous effect on white matter microstructure, where distinct patterns were found in the proximity of the lesions, in deep white matter and in white matter near the cortex. This study also raises several questions about the onset of WMH related pathology, in particular, whether some of the aberrant brain structural and microstructural findings are present before the emergence of WMH. We also found, similar to other studies, that WMH risk factors had low explanatory power for WMH, making it unclear which factors lead to WMH

The relation of hippocampal subfield volumes to verbal episodic memory measured by the California Verbal Learning Test II in healthy adults

Total hippocampal volume has previously been shown to correlate with performance on tests for verbal episodic memory. However, there are sparse evidence on how hippocampal subfield volumes are related to verbal episodic memory in healthy adults. The present study investigated the association between volumes of separate hippocampal subfields and verbal episodic memory performance in healthy volunteers. Forty-seven participants (31 females) between 20–71 years age underwent testing with the California Verbal Learning Test II (CVLT II), and the Wechsler Abbreviated Scale of Intelligence (WASI) to obtain an estimate of cognitive functioning. T1-weighted MR images were obtained after cognitive testing, and volumetric estimates adjusted for age and estimated total intracranial volume were calculated in the FreeSurfer 6.0 software suite for cerebral -and hippocampal structures. The sample performed within the statistical normal range on both CVLT II and WASI. Significant correlations adjusted for multiple testing were found between CVLT II subtests of total learning, free immediate recall and free delayed recall and volumes of the left Cornu Ammonis (CA) 1–4 subfields. There were no significant correlations between right hippocampal subfields and CVLT II performance, and no significant correlation between WASI results and hippocampal subfields. The present results suggest that better verbal episodic memory measured by the CVLT II is associated with relative larger volumes of specific left CA hippocampal subfields in healthy adults. Due to the small sample size and large age-span of the participants, the present findings are preliminary and should be confirmed in larger samples

An incomplete Circle of Willis is not a risk factor for white matter hyperintensities: The Tromsø Study

Objective - The Circle of Willis (CoW) is often underdeveloped or incomplete, leading to suboptimal blood supply to the brain. As hypoperfusion is thought to play a role in the aetiology of white matter hyperintensities (WMH), the objective of this study was to assess whether incomplete CoW variants were associated with increased WMH volumes compared to the complete CoW. Methods - In a cross-sectional population sample of 1751 people (age 40–84 years, 46.4% men), we used an automated method to segment WMH using T1-weighted and T2-weighted fluid-attenuated inversion recovery image obtained at 3T. CoW variants were classified from time-of-flight scans, also at 3T. WMH risk factors, including age, sex, smoking and blood pressure, were obtained from questionnaires and clinical examinations. We used linear regression to examine whether people with incomplete CoW variants had greater volumes of deep WMH (DWMH) and periventricular WMH (PWMH) compared to people with the complete CoW, correcting for WMH risk factors. Results - Participants with incomplete CoW variants did not have significantly higher DWMH or PWMH volumes than those with complete CoW when accounting for risk factors. Age, pack-years smoking, and systolic blood pressure were risk factors for increased DWMH and PWMH volume. Diabetes was a unique risk factor for increased PWMH volume. Conclusion - Incomplete CoW variants do not appear to be risk factors for WMH in the general population