Sandra Düzel

Vascular hippocampal plasticity after aerobic exercise in older adults

Aerobic exercise in young adults can induce vascular plasticity in the hippocampus, a critical region for recall and recognition memory. In a mechanistic proof-of-concept intervention over 3 months, we investigated whether healthy older adults (60–77 years) also show such plasticity. Regional cerebral blood flow (rCBF) and volume (rCBV) were measured with gadolinium-based perfusion imaging (3 Tesla magnetic resonance image (MRI)). Hippocampal volumes were assessed by high-resolution 7 Tesla MRI. Fitness improvement correlated with changes in hippocampal perfusion and hippocampal head volume. Perfusion tended to increase in younger, but to decrease in older individuals. The changes in fitness, hippocampal perfusion and volume were positively related to changes in recognition memory and early recall for complex spatial objects. Path analyses indicated that fitness-related changes in complex object recognition were modulated by hippocampal perfusion. These findings indicate a preserved capacity of the aging human hippocampus for functionally relevant vascular plasticity, which decreases with progressing age.

Relationships of peripheral IGF-1, VEGF and BDNF levels to exercise-related changes in memory, hippocampal perfusion and volumes in older adults

Animal models point towards a key role of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in mediating exercise-induced structural and functional changes in the hippocampus. Recently, also platelet derived growth factor-C (PDGF-C) has been shown to promote blood vessel growth and neuronal survival. Moreover, reductions of these neurotrophic and angiogenic factors in old age have been related to hippocampal atrophy, decreased vascularization and cognitive decline. In a 3-month aerobic exercise study, forty healthy older humans (60 to 77years) were pseudo-randomly assigned to either an aerobic exercise group (indoor treadmill, n=21) or to a control group (indoor progressive-muscle relaxation/stretching, n=19). As reported recently, we found evidence for fitness-related perfusion changes of the aged human hippocampus that were closely linked to changes in episodic memory function. Here, we test whether peripheral levels of BDNF, IGF-I, VEGF or PDGF-C are related to changes in hippocampal blood flow, volume and memory performance. Growth factor levels were not significantly affected by exercise, and their changes were not related to changes in fitness or perfusion. However, changes in IGF-I levels were positively correlated with hippocampal volume changes (derived by manual volumetry and voxel-based morphometry) and late verbal recall performance, a relationship that seemed to be independent of fitness, perfusion or their changes over time. These preliminary findings link IGF-I levels to hippocampal volume changes and putatively hippocampus-dependent memory changes that seem to occur over time independently of exercise. We discuss methodological shortcomings of our study and potential differences in the temporal dynamics of how IGF-1, VEGF and BDNF may be affected by exercise and to what extent these differences may have led to the negative findings reported here.

Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions

It is widely accepted that the brain and the immune system continuously interact during normal as well as pathological functioning. Human aging is commonly accompanied by low-grade inflammation in both the immune and central nervous systems, thought to contribute to many age-related diseases. This review of the current literature focuses first on the normal neuroimmune interactions occurring in the brain, which promote learning, memory and neuroplasticity. Further, we discuss the protective and dynamic role of barriers to neuroimmune interactions, which have become clearer with the recent discovery of the meningeal lymphatic system. Next, we consider age-related changes of the immune system and possible deleterious influences of immunosenescence and low-grade inflammation (inflammaging) on neurodegenerative processes in the normally aging brain. We survey the major immunomodulators and neuroregulators in the aging brain and their highly tuned dynamic and reciprocal interactions. Finally, we consider our current understanding of how physical activity, as well as a combination of physical and cognitive interventions, may mediate anti-inflammatory effects and thus positively impact brain aging.

Basal forebrain integrity and cognitive memory profile in healthy aging

Age-related dysfunctions in cholinergic and dopaminergic neuromodulation are assumed to contribute to age-associated impairment of explicit memory. Both neurotransmitters also modulate attention, working memory, and processing speed. To date, in vivo evidence linking structural age-related changes in these neuromodulatory systems to dysfunction within or across these cognitive domains remains scarce. Using a factor analytical approach in a cross-sectional study including 86 healthy older (aged 55 to 83 years) and 24 young (aged 18 to 30 years) adults, we assessed the relationship between structural integrity-as measured by magnetization transfer ratio (MTR)-of the substantia nigra/ventral tegmental area (SN/VTA), main origin of dopaminergic projections, basal forebrain (major origin of cortical cholinergic projections), frontal white matter (FWM), and hippocampus to neuropsychological and psychosocial scores. Basal forebrain MTR and FWM changes correlated with a factor combining verbal learning and memory and working memory and, as indicated by measures of diffusion, were most likely due to vascular pathology. These findings suggest that frontal white matter integrity and cholinergic neuromodulation provide clues as to why age-related cognitive decline is often correlated across cognitive domains.

MicroRNA-138 is a potential regulator of memory performance in humans

Genetic factors underlie a substantial proportion of individual differences in cognitive functions in humans, including processes related to episodic and working memory. While genetic association studies have proposed several candidate “memory genes,” these currently explain only a minor fraction of the phenotypic variance. Here, we performed genome-wide screening on 13 episodic and working memory phenotypes in 1318 participants of the Berlin Aging Study II aged 60 years or older. The analyses highlight a number of novel single nucleotide polymorphisms (SNPs) associated with memory performance, including one located in a putative regulatory region of microRNA (miRNA) hsa-mir-138-5p (rs9882688, P-value = 7.8 × 10−9). Expression quantitative trait locus analyses on next-generation RNA-sequencing data revealed that rs9882688 genotypes show a significant correlation with the expression levels of this miRNA in 309 human lymphoblastoid cell lines (P-value = 5 × 10−4). In silico modeling of other top-ranking GWAS signals identified an additional memory-associated SNP in the 3′ untranslated region (3′ UTR) of DCP1B, a gene encoding a core component of the mRNA decapping complex in humans, predicted to interfere with hsa-mir-138-5p binding. This prediction was confirmed in vitro by luciferase assays showing differential binding of hsa-mir-138-5p to 3′ UTR reporter constructs in two human cell lines (HEK293: P-value = 0.0470; SH-SY5Y: P-value = 0.0866). Finally, expression profiling of hsa-mir-138-5p and DCP1B mRNA in human post-mortem brain tissue revealed that both molecules are expressed simultaneously in frontal cortex and hippocampus, suggesting that the proposed interaction between hsa-mir-138-5p and DCP1B may also take place in vivo. In summary, by combining unbiased genome-wide screening with extensive in silico modeling, in vitro functional assays, and gene expression profiling, our study identified miRNA-138 as a potential molecular regulator of human memory function.

A close relationship between verbal memory and SN/VTA integrity in young and older adults

Age-related dysfunction in dopaminergic neuromodulation is assumed to contribute to age-associated memory impairment. However, to date there are no in vivo data on how structural parameters of the substantia nigra/ventral tegmental area (SN/VTA), the main origin of dopaminergic projections, relate to memory performance in healthy young and older adults. We investigated this relationship in a cross-sectional study including data from the hippocampus and frontal white matter (FWM) and also assessing working memory span and attention. In groups of young and older adults matched for the variance of their age distribution, gender and body mass index, we observed a robust positive correlation between Magnetization Transfer Ratio (MTR)--a measure of structural integrity--of the SN/VTA and FWM with verbal learning and memory performance among older adults, while there was a negative correlation in the young. Two additional imaging parameters, anisotropy of diffusion and diffusion coefficient, suggested that in older adults FWM changes reflected vascular pathology while SN/VTA changes pointed towards neuronal loss and loss of water content. The negative correlation in the young possibly reflected maturational changes. Multiple regression analyses indicated that in both young and older adults, SN/VTA MTR explained more variance of verbal learning and memory than FWM MTR or hippocampal MTR, and contributed less to explaining variance of working memory span. Together these findings indicate that structural integrity in the SN/VTA has a relatively selective impact on verbal learning and memory and undergoes specific changes from young adulthood to older age that qualitatively differ from changes in the FWM and hippocampus.

Cohort Differences in Psychosocial Function over 20 Years: Current Older Adults Feel Less Lonely and Less Dependent on External Circumstances.

Background: Lifespan psychological and life course sociological perspectives indicate that individual development is shaped by social and historical circumstances. Increases in fluid cognitive performance over the last century are well documented and researchers have begun examining historical trends in personality and subjective well-being in old age. Relatively less is known about secular changes in other key components of psychosocial function among older adults. Objective: In the present study, we examined cohort differences in key components of psychosocial function, including subjective age, control beliefs, and perceived social integration, as indicated by loneliness and availability of very close others. Methods: We compared data obtained 20 years apart in the Berlin Aging Study (in 1990-1993) and the Berlin Aging Study II (in 2013-2014) and identified case-matched cohort groups based on age, gender, cohort-normed education, and marital or partner status (n = 153 in each cohort, mean age = 75 years). In follow-up analyses, we controlled for having lived in former East versus West Germany, physical diseases, cohort-normed household income, cognitive performance, and the presence of a religious affiliation. Results: Consistently across analyses, we found that, relative to the earlier-born BASE cohort (year of birth: mean = 1916; SD = 3.38 years; range = 1901-1922), participants in the BASE-II sample (year of birth: mean = 1939; SD = 3.22 years; range = 1925-1949) reported lower levels of external control beliefs (d = -1.01) and loneliness (d = -0.63). Cohorts did not differ in subjective age, availability of very close others, and internal control beliefs. Conclusion: Taken together, our findings suggest that some aspects of psychosocial function of older adults have improved across the two recent decades. We discuss the possible role of sociocultural factors that might have led to the observed set of cohort differences.

Berlin Aging Studies (BASE and BASE-II)

The Berlin Aging Studies (BASE and BASE-II) are two consecutive studies of old age and aging with an interdisciplinary focus. The disciplines involved include psychology, psychiatry, geriatrics and internal medicine, genetics, sociology, and economics. The initial BASE data collection involved 14 sessions and took place in 1990–1993with 516men and women aged 70 to over 100 years. BASE-II currently involves five sessions with 1,600 older adults aged 60–80 years as well as 600 younger adults aged 20–35 years, who were assessed for the first time in 2011–2014. The initial Berlin Aging Study (BASE) was launched in 1989. In 1990–1993, 516 women and men aged 70 to 100+ years and living in the former West Berlin completed an intensive protocol of 14 sessions that exhaustively assessed their physical and mental health, life histories, living conditions, and psychological status. Subsequently, seven longitudinal follow-up assessments of surviving participants who had agreed to take part again were carried out until 2008/2009. In addition, mortality information was obtained regularly from the city registry. This allowed the examination of ageand death-related changes in old age. In 2011, a new study was launched, the Berlin Aging Study II (BASE-II), which focuses on many of the constructs examined in BASE as well as new constructs, but follows a larger group of old participants as well as a group of young adults for comparison. In the following, BASE and BASE-II are presented in depth, first focusing on BASE, and then drawing attention to select features of BASE-II.

Locus coeruleus integrity preserves memory performance across the adult life span

For decades, the search for drivers of memory decline in human cognitive aging has focused on neocortical regions, the hippocampus, and dopaminergic neuromodulation. Recent findings indicate that the locus coeruleus (LC) and noradrenergic neuromodulation may also play an important role in shaping memory development in later life. However, technical challenges in non-invasive monitoring of LC integrity have hindered the study of LC-cognition associations in humans so far. Using high-resolution neuromelanin-sensitive magnetic resonance imaging, we found that individual differences in learning and memory were positively associated with LC integrity across a variety of memory tasks in large samples of younger (n = 66), and older adults (n = 233). Moreover, we observed spatially confined and functionally relevant age differences in rostral LC. Older adults who showed a more youth-like rostral LC also showed higher memory performance. These findings link non-invasive, in vivo indices of LC integrity to memory in human aging and extend our knowledge about the role of the LC norepinephrine system in senescent decline in human cognition.For decades, research into memory decline in human cognitive aging has focused on neocortical regions, the hippocampus, and dopaminergic neuromodulation. Recent findings indicate that the locus coeruleus (LC) and noradrenergic neuromodulation may also play an important role in shaping memory development in later life. However, technical challenges in quantifying LC integrity have hindered the study of LC-cognition associations in humans. Using high-resolution neuromelanin-sensitive magnetic resonance imaging, we found that individual differences in learning and memory were positively associated with LC integrity across a variety of memory tasks in younger (n = 66), and older adults (n = 228). Moreover, we observed functionally relevant age differences confined to rostral LC. Older adults with a more youth-like rostral LC also showed higher memory performance. These findings link non-invasive, in vivo indices of LC integrity to memory in aging and highlight the role of the LC norepinephrine system in the decline of cognition.

Psychological and neural correlates of embitterment in old age

Objective: Posttraumatic embitterment disorder (PTED) comprises a stress-related response to a negative life event that violates the belief system of the individual. Characteristic symptoms involve repeated intrusive thoughts, emotional arousal when reminded of the event, and decreases in well-being. Method: Within the scope of the present study, embitterment was treated as a continuous rather than categorical concept, and we investigated its psychological and brain structural correlates in a sample of healthy older adults. Results: We found a negative association between the PTED self-rating score and self-reported well-being, life satisfaction, and future time perspective and a positive association with loneliness, perceived stress, chronic strain, and external control beliefs. We found no significant association between embitterment and brain regions that have been associated with stress exposure and posttraumatic stress disorder (PTSD)—hippocampus and the medial prefrontal cortex. This may emphasize the fundamental difference between PTED and PTSD. In a whole-brain analysis, we found a positive correlation between embitterment and gray matter volume in the precuneus and white matter volume in the bilateral uncinate fasciculus. Conclusions: The precuneus and uncinate fasciculus are brain regions that have been related to episodic memory retrieval, matching well to the symptoms of intrusive thoughts and an overwhelming preoccupation with the event that caused the PTED. Further longitudinal research is needed to unravel whether these structural correlates represent preconditions or rather the consequence of embitterment.