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Although age differences in the dopamine system have been suggested to contribute to age-related cognitive decline based on cross-sectional data, recent large-scale cross-sectional studies reported only weak evidence for a correlation among aging, dopamine receptor availability, and cognition. Regardless, longitudinal data remain essential to make robust statements about dopamine losses as a basis for cognitive aging. We present correlations between changes in D2/3 dopamine receptor availability and changes in working memory measured over 5 yr in healthy, older adults (n = 128, ages 64 to 68 yr at baseline). Greater decline in D2/3 dopamine receptor availability in working memory-relevant regions (caudate, middle frontal cortex, hippocampus) was related to greater decline in working memory performance in individuals who exhibited working memory reductions across time (n = 43; caudate: rs = 0.494; middle frontal cortex: rs = 0.506; hippocampus; rs = 0.423), but not in individuals who maintained performance (n = 41; caudate: rs = 0.052; middle frontal cortex: rs = 0.198; hippocampus; rs = 0.076). The dopamine–working memory link in decliners was not observed in the orbitofrontal cortex, which does not belong to the core working memory network. Our longitudinal analyses support the notion that aging-related changes in the dopamine system contribute to working memory decline in aging.

Higher-Level Gait Disorder (HLGD) is a type of gait disorder estimated to affect up to 6% of the older population. By definition, its symptoms originate from the higher-level nervous system, yet its association with brain morphology remains unclear. This study hypothesizes that there are patterns in brain morphology linked to HLGD. For the first time in the literature, this work investigates whether deep learning, in the form of convolutional neural networks, can capture patterns in magnetic resonance images to identify individuals affected by HLGD. To handle this new classification task, we propose setting up an ensemble of models. This leverages the benefits of combining classifiers instead of determining which network is the most suitable, developing a new architecture, or customizing an existing one. We introduce a computationally cost-effective search algorithm to find the optimal ensemble by leveraging a cost function of both traditional performance scores and the diversity among the models. Using a unique dataset from a large population-based cohort (VESPR), the ensemble identified by our algorithm demonstrated superior performance compared to single networks, other ensemble fusion techniques, and the best linear radiological measure. This emphasizes the importance of implementing diversity into the cost function. Furthermore, the results indicate significant morphological differences in brain structure between HLGD-affected individuals and controls, motivating research about which areas the networks base their classifications on, to get a better understanding of the pathophysiology of HLGD.

Background: Normal brain aging is associated with dopamine decline, which has been linked to age-related cognitive decline. Factors underlying individual differences in dopamine integrity at older ages remain, however, unclear. Here we aimed at investigating: (i) whether inflammation is associated with levels and 5-year changes of in vivo dopamine D2-receptor (DRD2) availability, (ii) if DRD2-inflammation associations differ between men and women, and (iii) whether inflammation and cerebral small-vessel disease (white-matter lesions) serve as two independent predictors of DRD2 availability.

Methods: Analyses were performed in a sample of healthy adults > 60 years assessed at two measurement occasions separated by 5 years. At both occasions, DRD2 availability was estimated by ¹¹C-raclopride PET, and white-matter lesions by MRI. Inflammation was assessed by two C-reactive protein-associated DNA methylation scores at study baseline.

Results: Individuals with higher DNA methylation scores at baseline showed reduced striatal DRD2 availability. An interaction was found between DNA methylation scores and sex in relation to striatal DRD2 availability, such that associations were found in men but not in women. DNA methylation scores at study entrance were not significantly associated with 5-year striatal DRD2 decline rates. No significant association was found between DNA methylation scores and white-matter lesions, but higher scores as well as higher lesion burden were independently associated with reduced striatal DRD2 availability in men.

Conclusions: These findings suggest negative associations between one proxy of inflammation and DRD2 availability in older adults, selectively for men who had higher DNA methylation scores. Future studies should investigate other inflammatory markers in relation to dopamine integrity.

Background: Induced hypertension is used clinically to increase cerebral blood flow (CBF) in conditions such as vasospasm after subarachnoid hemorrhage. However, increased blood pressure also raises pulsatile force. Cerebrovascular compliance plays a key role in buffering flow dynamics and protecting the microcirculation, but whether it adapts to elevated pressure remains unclear. This study assessed the response of compliant cerebral arteries to induced hypertension in healthy adults using phase-contrast magnetic resonance imaging (PCMRI) and two compliance models: a two-element Windkessel (CWK) and a simplified model (CVP), representing the extremes of pulsatility transmission at the capillary level.

Methods: Eighteen healthy adults (median age: 34 years; 9 females) underwent PCMRI at baseline and after increasing mean arterial pressure by 20% using norepinephrine (NE) infusion. PCMRI quantified CBF and cardiac output, while cerebrovascular resistance and systemic vascular resistance were derived. Flow waveforms were combined with blood pressure to assess CWK and CVP in CBF, ascending/descending aorta, and external carotid arteries, while corresponding regions of interest were used to calculate cross-sectional flow areas. Data are reported as median (interquartile range).

Results: NE increased cerebrovascular compliance significantly; CWK by 110% (56% to 163%; P=0.001) and CVP by 11% (−2% to 26%; P=0.018). CWK increased in the external carotid artery by 12% (1% to 32%; P=0.037) but did not change in the ascending or descending aorta. CVP decreased in the descending aorta by 5% (-11% to 2%; P=0.028), with no changes in the ascending aorta or external carotid artery. Cross-sectional area of cerebral arteries contributing to CBF decreased by 5% (-17% to -3%; P=0.033), while the ascending and descending aorta areas increased by 7% (4% to 11%; P=0.012) and 8% (6% to 11%; P<0.001), respectively.

Conclusion: Cerebral arteries enhanced their compliance during NE-induced hypertension, unlike systemic arteries, regardless of the assumed degree of pulsatility transmission.

Normal aging is associated with decline in dopamine function. Factors associated with individual differences in dopamine decline rates remain unclear but are important to map to spare dopamine-related functions, such as cognition. Here we focused on manifestations of cerebral small-vessel disease from magnetic resonance imaging (white-matter lesions, lacunes, and perivascular space dilation) and vascular risk factors (e.g., hypertension, body mass index (BMI), and hyperlipidemia). We assessed striatal dopamine D2-like receptor (DRD2) reductions across five years in healthy, older adults (n = 129, ages: 64–68 years at baseline) using 11C-raclopride/positron emission tomography. Manifestations of confluent lesions and lacunes at baseline had additive effects on DRD2 decline. Individuals with both manifestations showed fastest DRD2 decline rates (∼ −4 %), followed by those with one manifestation (∼ −2 %), whereas individuals spared of confluent lesions and lacunes showed stable DRD2 levels over time (∼ 0 % change). Furthermore, individuals with confluent lesions or lacunes showed more marked decline in perceptual speed performance, as compared to individuals spared of these manifestations (p < 0.05). Higher systolic blood pressure and lower BMI at baseline were associated with faster 5-year DRD2 decline in the putamen (r = -0.17, p < 0.05) and caudate (r = 0.23, p < 0.05), respectively. Together, confluent lesions and lacunes explained up to 8 % of striatal DRD2 change, and up to 10 % when adding hypertension and BMI to the model. These findings suggest that hallmarks of SVD and certain vascular risk factors predispose faster DRD2 decline in aging and may thus serve as factors to consider in future interventions.

Background: White matter lesions (WML) and dilated perivascular spaces (PVS) are features of small vessel disease (SVD), commonly observed in aging and dementia, with unknown pathophysiology. Human studies have documented contrast accumulation within and in proximity of SVD-lesions. However, whether such observations mainly reflect excessive blood-brain barrier (BBB) leakage, or altered microvascular density in the investigated regions, remains unclear.

Methods: To evaluate the roles of BBB leakage and vascular density in aging and SVD, dynamic contrast enhanced (DCE) MRI was used to estimate the permeability-surface area product (PS) and fractional plasma volume () in normal-appearing brain tissue and in proximity of and within WML and PVS in a population-based cohort (N = 56; 34/22 m/f; age 64 to 84 years). Analysis of variance (ANOVA) was used to assess regional differences in PS and and analysis of covariance (ANCOVA) was used to assess regional differences in PS with and vascular risk as covariates.

Results: Pronounced increases in PS and were observed from normal-appearing white matter (NAWM) to WML peripheries to WMLs. Similar PS and increases were observed from basal ganglia (BG) to BG-PVS. Further, PS in NAWM and white matter (WM) PVS were found to increase with cortex-to-ventricular depth. However, ANCOVA models with as a covariate showed that variance in PS was mainly explained by vp (η2=0.17 to η2=0.35; all p < 10− 3), whereas the effect of region was only borderline-significant when comparing NAWM, WML peripheries and WML (p = 0.03) and non-significant for the other comparisons (p > 0.29).

Conclusions: Our findings support the notion that contrast leakage across the BBB accumulates within and in proximity of SVD-related lesions. However, high contrast accumulation may mainly reflect high vascularization, and to a lesser degree than previously recognized BBB dysfunction.

Selective antegrade cerebral perfusion (SACP) is a protective procedure to ascertain adequate brain perfusion during aortic arch surgeries requiring moderate hypothermic circulatory arrest. SACP entails catheterization of arteries feeding the brain, which can be done bilaterally (bSACP) or unilaterally (uSACP), but there is no consensus on when to use each approach. bSACP may increase the risk of embolization, while uSACP risks hypoperfusion due to insufficient perfusion pressure in the contralateral hemisphere, since a single catheter must perfuse both hemispheres. We developed and tested the feasibility of a new method for predicting cerebral perfusion pressures (CPP) during SACP, which could potentially aid clinicians in preoperatively identifying which SACP approach to use. Feasibility of the method was evaluated in five patients eligible for aortic arch surgery (65 ± 7 years, 3 men). Patients were investigated preoperatively with computed tomography angiography (CTA) and 4D flow magnetic resonance imaging (MRI) to assess patient-specific arterial anatomy and blood flows. From the imaging, computational fluid dynamics (CFD) simulations estimated the patients' vascular resistances. Applying these resistances and intraoperative SACP pressure/flow settings to the model's boundary conditions allowed for predictions of contralateral CPP during SACP. Predicted pressures were compared to corresponding intraoperative pressure measurements. The method showed promise for predicting contralateral CPP during both uSACP (median error (range): 2.4 (−0.2–18.0) mmHg) and bSACP (0.8 (−3.3–5.4) mmHg). Predictions were most sensitive to collateral artery size. This study showed the feasibility of CPP predictions of SACP, and presents key features needed for accurate modelling.

Background and purpose: Disproportionately enlarged subarachnoid space hydrocephalus (DESH) is a radiological biomarker for idiopathic normal pressure hydrocephalus (iNPH). DESH is a subjective measure, based on visual assessments, which may limit its reliability. The aim of this study was to develop and validate a method for the objective quantification of DESH.

Materials and methods: By using a semiautomatic quantitative method, we calculated quantitative DESH (qDESH), defined as a ratio between CSF volumes at high convexities and Sylvian fissures. The analysis was based on three-dimensional T1-weighted images from 35 subjects with iNPH (mean age 74 yrs; 10 females) and 45 controls (mean age 72 yrs; 13 females). The interrater agreement for qDESH was evaluated by the intraclass correlation coefficient, and qDESH was compared with visual assessments performed by two neuroradiologists.

Results: All subjects with iNPH and 13% of the controls visually scored DESH positive. The median qDESH was 2.48 (5th to 95th percentile 0.88 to 5.42) for iNPH and 0.63 (5th to 95th percentile 0.37 to 1.73) for the controls. The area under the receiver operating characteristic curve for qDESH was 0.95 (95% confidence interval 0.90–1) in separating iNPH patients from controls. The interrater agreement for qDESH was 0.99 (95% CI 0.986–0.994, p < 0.001).

Conclusion: Unlike visual DESH, qDESH generates a continuous variable, enabling reproducible quantification of DESH severity. With this method we can objectively investigate the diagnostic accuracy and prognostic assessment of DESH in iNPH.

Variations in cerebral blood flow and blood volume interact with intracranial pressure and cerebrospinal fluid dynamics, all of which play a crucial role in brain homeostasis. A key physiological modulator is respiration, but its impact on cerebral blood flow and volume has not been thoroughly investigated. Here we used 4D flow MRI in a population-based sample of 65 participants (mean age = 75 ± 1) to quantify these effects. Two gating approaches were considered, one using respiratory-phase and the other using respiratory-time (i.e. raw time in the cycle). For both gating methods, the arterial inflow was significantly larger during exhalation compared to inhalation, whereas the venous outflow was significantly larger during inhalation compared to exhalation. The cerebral blood volume variation per respiratory cycle was 0.83 [0.62, 1.13] ml for respiratory-phase gating and 0.78 [0.59, 1.02] ml for respiratory-time gating. For comparison, the volume variation of the cardiac cycle was 1.01 [0.80, 1.30] ml. Taken together, our results clearly demonstrate respiratory influences on cerebral blood flow. The corresponding vascular volume variations appear to be of the same order of magnitude as those of the cardiac cycle, highlighting respiration as an important modulator of cerebral blood flow and blood volume.

Blood-brain barrier (BBB) disruption may contribute to cognitive decline, but questions remain whether this association is more pronounced for certain brain regions, such as the hippocampus, or represents a whole-brain mechanism. Further, whether human BBB leakage is triggered by excessive vascular pulsatility, as suggested by animal studies, remains unknown. In a prospective cohort (N = 50; 68-84 years), we used contrast-enhanced MRI to estimate the permeability-surface area product (PS) and fractional plasma volume ( formula presented ), and 4D flow MRI to assess cerebral arterial pulsatility. Cognition was assessed by the Montreal Cognitive Assessment (MoCA) score. We hypothesized that high PS would be associated with high arterial pulsatility, and that links to cognition would be specific to hippocampal PS. For 15 brain regions, PS ranged from 0.38 to 0.85 (·10-3 min-1) and formula presented from 0.79 to 1.78%. Cognition was related to PS (·10-3 min-1) in hippocampus (β = - 2.9; p = 0.006), basal ganglia (β = - 2.3; p = 0.04), white matter (β = - 2.6; p = 0.04), whole-brain (β = - 2.7; p = 0.04) and borderline-related for cortex (β = - 2.7; p = 0.076). Pulsatility was unrelated to PS for all regions (p > 0.19). Our findings suggest PS-cognition links mainly reflect a whole-brain phenomenon with only slightly more pronounced links for the hippocampus, and provide no evidence of excessive pulsatility as a trigger of BBB disruption.