Age-related changes to lumbosacral spinal cord motoneurons that modulate bladder and bowel functions in male C57BL/6 mice

Incontinence and sexual dysfunction are often increased in the aged human population. In rats and mice the pattern of micturition and faecal clearance also changes with ageing and is suggestive of bladder and bowel dysfunction

Age-related changes in blood-brain barrier integrity in C57BL/6J mice

The blood-brain barrier (BBB) is formed by the endothelial cells of the brain microvasculature, which control the molecular traffic between the blood and brain to maintain the neural microenvironment

Ultrastructural analysis of changes in neurons of the mouse internal anal sphincter during ageing

Gastrointestinal disorders, including chronic constipation, faecal impaction and incontinence, are a major cause of morbidity in the elderly

The association of dietary patterns with cognition through the lens of neuroimaging—a systematic review

Despite the reported benefits of diet on cognition in older adults, randomized controlled trials (RCT) testing the impact of dietary interventions on cognitive scores have yielded less promising results when cognition was assessed via neuropsychological tests. More recently, neuroimaging has been used to identify more subtle brain-related changes associated to cognition. Hence, employing a combination of neuroimaging techniques with neuropsychological tests could clarify this controversy. To determine the effect of diet on cognitive performance, we conducted a systematic review of PubMed and Scopus databases for all studies, on middle-aged and older adults, combining neuroimaging, neuropsychological tests, and data on dietary patterns. The inclusion criteria were met by 14 observational studies and no RCTs. The range of brain measures assessed varied from volumes to white matter integrity, functional connectivity, brain glucose metabolism and beta-amyloid deposition. Given the variability of methods used in assessing cognitive performance, diet and brain correlates, conducting a meta-analysis was not possible. Here the evidence suggests that, in observational studies, dietary patterns may be associated with brain correlates that have been shown to precede cognitive decline. As such, neuroimaging should be included in future RCTs to identify any benefits of diet on brain measures linked with cognitive health

Sex Differences in the Influence of Brain and Lifestyle Factors on Neurocognitive Aging

Declines in executive functioning (EF) are a hallmark of neurocognitive aging. Much research has focused on the impact of exercise, brain structure, and brain function on neurocognitive aging, yet their relative predictive weights had not been evaluated. Further, the impact of sex differences on the influence of these factors had not yet been investigated. Fifty-one older adults participated in this study evaluating the outcome of cardiorespiratory fitness (CRF), prefrontal cortex volume, and global efficiency of functional brain networks on EF. A stratified, multiple hierarchical regression was performed to identify the best predictors of EF for each sex. For females, a model containing solely CRF served as the best predictor of EF. A model containing both CRF and network efficiency best predicted EF in males. These results demonstrate that CRF and metrics of structural and functional brain health in older adulthood are independently associated with EF in a sex-dependent manner

Dietary and serum tyrosine, white matter microstructure and inter-individual variability in executive functions in overweight adults: Relation to sex/gender and age

Tyrosine (tyr), the precursor of the neurotransmitter dopamine, is known to modulate cognitive functions including executive attention. Tyr supplementation is suggested to influence dopamine-modulated cognitive performance. However, results are inconclusive regarding the presence or strength and also the direction of the association between tyr and cognitive function. This pre-registered cross-sectional analysis investigates whether diet-associated serum tyr relates to executive attention performance, and whether this relationship is moderated by differences in white matter microstructure. 59 healthy, overweight, young to middle-aged adults (20 female, 28.3 ± 6.6 years, BMI: 27.3 ± 1.5 kg/m2) drawn from a longitudinal study reported dietary habits, donated blood and completed diffusion-weighted brain magnetic resonance imaging and the attention network test. Main analyses were performed using linear regressions and non-parametric voxel-wise inference testing. Confirmatory analyses did neither support an association between dietary and serum tyr nor a relationship between relative serum tyr/large neutral amino acids (LNAA) levels or white matter microstructure and executive attention performance. However, exploratory analyses revealed higher tyr intake, higher serum tyr and better executive attention performance in the male sex/gender group. In addition, older age was associated with higher dietary tyr intake and lower fractional anisotropy in a widespread cluster across the brain. Finally, a positive association between relative serum tyr/LNAA and executive attention performance was found in the male sex/gender group when accounting for age effects. Our analysis advances the field of dopamine-modulated cognitive functions by revealing sex/gender and age differences which might be diet-related. Longitudinal or intervention studies and larger sample sizes are needed to provide more reliable evidence for links between tyr and executive attention

Evaluation and implementation of functional cerebral biomarkers in Alzheimer’s disease

The aim of this thesis was to evaluate and implement functional cerebral biomarkers in Alzheimer’s disease (AD) with respect to pathophysiology, disease severity, prognosis and treatment effect in medical trials. We focused on functional cerebral biomarkers that assess synaptic activity and functional connectivity using electroencephalography (EEG), magnetoencephalography (MEG) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET). In the different chapters a broad range of challenges associated with this topic was covered. We started by using FDG- PET to observe the effects of the experimental treatment of AD patients with the medical food Souvenaid, followed by EEG as treatment outcome measure in a trial with the drug PQ912. Next to the primary outcomes, the results of these studies revealed that more research was needed to observe which markers could observe reliable, reproducible and valid results and what the factors were that could influence their ability to do this. The EEG markers, rather than the FDG- PET markers, showed promising results. Therefore, we aimed to investigate the effects of sensitivity, reproducibility, heterogeneity of the population and treatment efficacy, while maintaining a well-defined study population and study design, on EEG biomarkers. We first investigated the reproducibility of AD related changes in functional connectivity captured by different measures in electroencephalography (EEG) and magnetoencephalography (MEG). Second, we evaluated the influence of subtypes of AD on various EEG measures and, on the other hand, we used EEG to find heterogeneity and to predict clinical progression

Effects of Obesity and Weight Loss Following Bariatric Surgery on Brain Function, Structural Integrity and Metabolism

Obesity is one of the key challenges to health care system worldwide and its prevalence is estimated to rise to pandemic proportions. Numerous adverse health effects follow with increasing body weight, including increased risk of hypertension, diabetes, hypercholesterolemia, musculoskeletal pain and cancer. Current evidence suggests that obesity is associated with altered cerebral reward circuit functioning and decreased inhibitory control over appetitive food cues. Furthermore, obesity causes adverse shifts in metabolism and loss of structural integrity within the brain. Prior cross-sectional studies do not allow delineating which of these cerebral changes are recoverable after weight loss. We compared morbidly obese subjects with healthy controls to unravel brain changes associated with obesity. Bariatric surgery was used as an intervention to study which cerebral changes are recoverable after weight loss. In Study I we employed functional magnetic resonance imaging (fMRI) to detect the brain basis of volitional appetite control and its alterations in obesity. In Studies II-III we used diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) to quantify the effects of obesity and the effects of weight loss on structural integrity of the brain. In study IV we used positron emission tomography (PET) with [18F]-FDG in fasting state and during euglycemic hyperinsulinemia to quantify effects of obesity and weight loss on brain glucose uptake. The fMRI experiment revealed that a fronto-parietal network is involved in volitional appetite control. Obese subjects had lower medial frontal and dorsal striatal brain activity during cognitive appetite control and increased functional connectivity within the appetite control circuit. Obese subjects had initially lower grey matter and white matter densities than healthy controls in VBM analysis and loss of integrity in white matter tracts as measured by DTI. They also had initially elevated glucose metabolism under insulin stimulation but not in fasting state. After the weight loss following bariatric surgery, obese individuals’ brain volumes recovered and the insulin-induced increase in glucose metabolism was attenuated. In conclusion, obesity is associated with altered brain function, coupled with loss of structural integrity and elevated glucose metabolism, which are likely signs of adverse health effects to the brain. These changes are reversed by weight loss after bariatric surgery, implicating that weight loss has a causal role on these adverse cerebral changes. Altogether these findings suggest that weight loss also promotes brain health.Key words: brain, obesity, bariatric surgery, appetite control, structural magnetic resonanceLihavuus yleistyy nopeasti koko maailmassa ja se on yksi suurimmista terveydenhuollon tulevaisuuden haasteista. Lihavuus lisää riskiä sairastua useisiin sairauksiin mm. verenpainetautiin, diabetekseen, tuki- ja liikuntaelinten sairauksiin ja useisiin syöpiin. Lihavilla on havaittu aivojen palkkiojärjestelmän reagoivan yliaktiivisesti ruokaan liittyviin ärsykkeisiin ja toisaalta ruokahalua hillitsevien alueiden toiminnan on havaittu olevan heikompaa kuin normaalipainoisilla. Lihavuus aiheuttaa myös haitallisia muutoksia aivosolujen rakenteessa ja aineenvaihdunnassa. Näiden muutosten palautumispotentiaalia ei voida arvioida poikkileikkaustutkimuksissa. Tässä työssä tutkimme sairaalloisen lihavia lihavuusleikkaukseen valittuja potilaita, joiden aivokuvantamistuloksia verrattiin normaalipainoisten vastaaviin kuvauksiin. Potilaat tutkittiin myös kuusi kuukautta lihavuusleikkauksen jälkeen painonlaskun aiheuttamien aivomuutosten tutkimiseksi. Ensimmäisessä tutkimuksessa ruokahalun säätelyjärjestelmän toiminnan ja lihavuuden aiheuttamien muutosten selvittämiseksi käytettiin toiminnallista magneettikuvantamista (fMRI). Rakenteellisia muutoksia arvioitiin II ja III osatyössä diffuusiotensorikuvantamisella (DTI) sekä vokseliperustaisen morfometrian avulla (VBM). Neljännessä osatyössä aivojen sokeriaineenvaihduntaa tutkittiin positroniemissiotomografian (PET) avulla käyttämällä [18F]-FDG-merkkiainetta paastotilassa ja insuliini-stimulaation aikana. VBM -ja PET-menetelmiä käytettiin myös lihavuusl eikkauksen vaikutusten arviointiin. fMRI-kokeessa havaittiin, että ruokahalun säätelyyn osallistuu laaja hermoverkko jonka keskeiset osat sijoittuvat otsa- ja päälaenlohkoihin. Lihavilla tutkittavilla havaittiin alentuneet vasteet häntätumakkeessa ja etupihtipoimun alueella. Lisäksi heillä havaittiin voimakkaammat toiminnalliset yhteydet ruokahalun säätelyverkostossa. Lihavuus aiheuttaa aivoissa laajaa aivokudoksen harventumaa ja hermoratojen eheyden alentumaa. PET-tutkimuksessa havaittiin lihavuuden lisäävän aivojen insuliiniherkkyyttä. Puoli vuotta lihavuusleikkauksen jälkeen rakenteelliset ja aineenvaihdunnan muutokset palautuivat osittain.Siirretty Doriast

Aging, Executive Function, Fronto-Parietal Network Cortical Thickness: Insights from Cognitive Reserve

Cognitive reserve (CR) indexes the nonlinear relationship between neurological insult and behavioral change. CR is manifested in both static factors (e.g., childhood environment, education) and modifiable lifestyle factors, (e.g., leisure activities). Detailed investigation of the influence of CR on cortical thickness, which indexes neuropathology, and cognitive functioning could be particularly important in understanding the heterogeneity of Alzheimer’s disease (AD). While memory decline is the hallmark of AD, executive functioning (EF) decline often predates memory changes, making EF an important target for investigating CR influences. The current study examines the relationship of CR and genetic risk for AD (ε4) on EF as it relates to fronto-parietal neural network cortical thickness, and memory performance as it relates to medial temporal lobe thickness and hippocampal volume. This study addresses the heterogeneity of CR measurement by examining three different CR factors (CR1=IQ; CR2=IQ, Activities, CR3=IQ, Activities, Health) in 35 healthy elders age 51-84 (19 ε4+/16 ε4-). High CR was associated with better cognition. CR2 was associated with memory and CR3 was predictive of EF. High CR was also associated with greater cortical thickness: CR1 with cingulate; CR2 with inferior and superior parietal; and CR3 with insula, inferior and superior parietal. Across all CR measures, the interaction of ε4 and CR was associated with insula, inferior and superior parietal thickness. CR2 and CR3 further revealed interactions within frontal regions: CR1 and CR2 were associated with right parahippocampal gyrus (PHG), CR2 with left hippocampus, and CR3 with left PHG. Some regions showed an ‘Additive Benefit’, where high CR was particularly beneficial to ε4 carriers, while others showed an ‘Additive Detriment’, where low CR was particularly detrimental to ε4 carriers. This study also demonstrated that different CR measures yield disparate results. Nevertheless, CR was beneficial to both cognitive functioning and cortical thickness, particularly in ε4 carriers. Results are clinically translatable to identify mechanisms to delay the onset of AD