Non-pathological Aging Research Articles

Age-related neural changes underlying long-term recognition of musical sequences

Aging is often associated with decline in brain processing power and neural predictive capabilities. To challenge this notion, we used magnetoencephalography (MEG) and magnetic resonance imaging (MRI) to record the whole-brain activity of 39 older adults (over 60 years old) and 37 young adults (aged 18–25 years) during recognition of previously memorised and varied musical sequences. Results reveal that when recognising memorised sequences, the brain of older compared to young adults reshapes its functional organisation. In fact, it shows increased early activity in sensory regions such as the left auditory cortex (100 ms and 250 ms after each note), and only moderate decreased activity (350 ms) in medial temporal lobe and prefrontal regions. When processing the varied sequences, older adults show a marked reduction of the fast-scale functionality (250 ms after each note) of higher-order brain regions including hippocampus, ventromedial prefrontal and inferior temporal cortices, while no differences are observed in the auditory cortex. Accordingly, young outperform older adults in the recognition of novel sequences, while no behavioural differences are observed with regards to memorised ones. Our findings show age-related neural changes in predictive and memory processes, integrating existing theories on compensatory neural mechanisms in non-pathological aging.

The impact of a tDCS and cognitive training intervention on task-based functional connectivity.

Declines in several cognitive domains, most notably processing speed, occur in non-pathological aging. Given the exponential growth of the older adult population, declines in cognition serve as a significant public health issue that must be addressed. Promising studies have shown that cognitive training in older adults, particularly using the useful field of view (UFOV) paradigm, can improve cognition with moderate to large effect sizes. Additionally, meta-analyses have found that transcranial direct current stimulation (tDCS), a non-invasive form of brain stimulation, can improve cognition in attention/processing speed and working memory. However, only a handful of studies have looked at concomitant tDCS and cognitive training, usually with short interventions and small sample sizes. The current study assessed the effect of a tDCS (active versus sham) and a 3-month cognitive training intervention on task-based functional connectivity during completion of the UFOV task in a large older adult sample (N = 153). We found significant increased functional connectivity between the left and right pars triangularis (the ROIs closest to the electrodes) following active, but not sham tDCS. Additionally, we see trending behavioral improvements associated with these functional connectivity changes in the active tDCS group, but not sham. Collectively, these findings suggest that tDCS and cognitive training can be an effective modulator of task-based functional connectivity above and beyond a cognitive training intervention alone.

9 Connecting memory and functional brain networks in older adults: a resting state fMRI study

Objective:Nonpathological aging has been linked to decline in both verbal and visuospatial memory abilities in older adults. Disruptions in resting-state functional connectivity within well-characterized, higherorder cognitive brain networks have also been coupled with poorer memory functioning in healthy older adults and in older adults with dementia. However, there is a paucity of research on the association between higherorder functional connectivity and verbal and visuospatial memory performance in the older adult population. The current study examines the association between resting-state functional connectivity within the cingulo-opercular network (CON), frontoparietal control network (FPCN), and default mode network (DMN) and verbal and visuospatial learning and memory in a large sample of healthy older adults. We hypothesized that greater within-network CON and FPCN functional connectivity would be associated with better immediate verbal and visuospatial memory recall. Additionally, we predicted that within-network DMN functional connectivity would be associated with improvements in delayed verbal and visuospatial memory recall. This study helps to glean insight into whether within-network CON, FPCN, or DMN functional connectivity is associated with verbal and visuospatial memory abilities in later life.Participants and Methods:330 healthy older adults between 65 and 89 years old (mean age = 71.6 ± 5.2) were recruited at the University of Florida (n = 222) and the University of Arizona (n = 108). Participants underwent resting-state fMRI and completed verbal memory (Hopkins Verbal Learning Test - Revised [HVLT-R]) and visuospatial memory (Brief Visuospatial Memory Test - Revised [BVMT-R]) measures. Immediate (total) and delayed recall scores on the HVLT-R and BVMT-R were calculated using each test manual’s scoring criteria. Learning ratios on the HVLT-R and BVMT-R were quantified by dividing the number of stimuli (verbal or visuospatial) learned between the first and third trials by the number of stimuli not recalled after the first learning trial. CONN Toolbox was used to extract average within-network connectivity values for CON, FPCN, and DMN. Hierarchical regressions were conducted, controlling for sex, race, ethnicity, years of education, number of invalid scans, and scanner site.Results:Greater CON connectivity was significantly associated with better HVLT-R immediate (total) recall (ß = 0.16, p = 0.01), HVLT-R learning ratio (ß = 0.16, p = 0.01), BVMT-R immediate (total) recall (ß = 0.14, p = 0.02), and BVMT-R delayed recall performance (ß = 0.15, p = 0.01). Greater FPCN connectivity was associated with better BVMT-R learning ratio (ß = 0.13, p = 0.04). HVLT-R delayed recall performance was not associated with connectivity in any network, and DMN connectivity was not significantly related to any measure.Conclusions:Connectivity within CON demonstrated a robust relationship with different components of memory function as well across verbal and visuospatial domains. In contrast, FPCN only evidenced a relationship with visuospatial learning, and DMN was not significantly associated with memory measures. These data suggest that CON may be a valuable target in longitudinal studies of age-related memory changes, but also a possible target in future non-invasive interventions to attenuate memory decline in older adults.

Age-dependent Effects of Dopamine on Working Memory and Synaptic Plasticity in Hippocampal CA3-CA1 Synapses in Mice.

Normal aging in mammals is accompanied by a decline in learning and memory. Dopamine plays a vital role in regulating cognitive functions, but it declines with age: During non-pathological aging, dopamine levels, receptors, and transporters decrease. Regarding the role of the dopaminergic system's changes in old age, we examined the effect of age and applied dopamine on working memory, synaptic transmission, and long-term potentiation (LTP) induction and maintenance in young adult and mature adult mice. We employed the Y-maze spontaneous alteration test to evaluate working memory. Maturation had no observed effect on working memory performance. Interestingly, working memory performance increased following intracerebroventricular administration of dopamine only in mature adult mice. We employed evoked field potential recording (in vitro) to assess the effects of age and maturation on the long-term potentiation (LTP) induction and maintenance. There was no difference in LTP induction and maintenance between young and mature adult mice before dopamine application. However, the application of dopamine on mature adult murine slices increased LTP magnitude compared to slices from young adults. According to the obtained results, it may be concluded that hippocampal neural excitability increased in mature adult subjects, and application of dopamine abolished the difference in neural excitability among young mature and adult mature groups; which was accompanied with increment of working memory and synaptic potentiation in mature adult animals.

How Does Aging Affect Whole-brain Functional Network Connectivity? Evidence from An ICA Method.

Many studies have shown that changes in the functional connectivity are diverse along with aging. However, few studies have addressed how aging affects connectivity among large-scale brain networks, and it is challenging to examine gradual aging trajectories from middle adulthood to old age. In this work, based on large-sample fMRI data from 6300 subjects aged between 49 to 73 years, we apply an independent component analysis-based method called NeuroMark to extract brain functional networks and their connectivity (i.e., functional network connectivity (FNC)), and then propose a two-level statistical analysis method to explore robust aging-related changes in functional network connectivity. We found that the enhanced FNCs mainly occur between different functional domains, involving the default mode and cognitive control networks, while the reduced FNCs come from not only between different domains but also within the same domain, primarily relating to the visual network, cognitive control network and cerebellum. Our results emphasize the diversity of brain aging and provide new evidence for non-pathological aging of the whole brain.Clinical Relevance-This provides new evidence for non-pathological aging of functional network connectivity in the whole brain.

Aging brain shows joint declines in brain within-network connectivity and between-network connectivity: a large-sample study (N > 6,000).

Numerous studies have shown that aging has important effects on specific functional networks of the brain and leads to brain functional connectivity decline. However, no studies have addressed the effect of aging at the whole-brain level by studying both brain functional networks (i.e., within-network connectivity) and their interaction (i.e., between-network connectivity) as well as their joint changes. In this work, based on a large sample size of neuroimaging data including 6300 healthy adults aged between 49 and 73 years from the UK Biobank project, we first use our previously proposed priori-driven independent component analysis (ICA) method, called NeuroMark, to extract the whole-brain functional networks (FNs) and the functional network connectivity (FNC) matrix. Next, we perform a two-level statistical analysis method to identify robust aging-related changes in FNs and FNCs, respectively. Finally, we propose a combined approach to explore the synergistic and paradoxical changes between FNs and FNCs. Results showed that the enhanced FNCs mainly occur between different functional domains, involving the default mode and cognitive control networks, while the reduced FNCs come from not only between different domains but also within the same domain, primarily relating to the visual network, cognitive control network, and cerebellum. Aging also greatly affects the connectivity within FNs, and the increased within-network connectivity along with aging are mainly within the sensorimotor network, while the decreased within-network connectivity significantly involves the default mode network. More importantly, many significant joint changes between FNs and FNCs involve default mode and sub-cortical networks. Furthermore, most synergistic changes are present between the FNCs with reduced amplitude and their linked FNs, and most paradoxical changes are present in the FNCs with enhanced amplitude and their linked FNs. In summary, our study emphasizes the diversity of brain aging and provides new evidence via novel exploratory perspectives for non-pathological aging of the whole brain.

Loss of smelling is an early marker of aging and is associated with inflammation and DNA damage in C57BL/6J mice.

Olfactory dysfunction is a prevalent symptom and an early marker of age-related neurodegenerative diseases in humans, including Alzheimer's and Parkinson's Diseases. However, as olfactory dysfunction is also a common symptom of normal aging, it is important to identify associated behavioral and mechanistic changes that underlie olfactory dysfunction in nonpathological aging. In the present study, we systematically investigated age-related behavioral changes in four specific domains of olfaction and the molecular basis in C57BL/6J mice. Our results showed that selective loss of odor discrimination was the earliest smelling behavioral change with aging, followed by a decline in odor sensitivity and detection while odor habituation remained in old mice. Compared to behavioral changes related with cognitive and motor functions, smelling loss was among the earliest biomarkers of aging. During aging, metabolites related with oxidative stress, osmolytes, and infection became dysregulated in the olfactory bulb, and G protein coupled receptor-related signaling was significantly down regulated in olfactory bulbs of aged mice. Poly ADP-ribosylation levels, protein expression of DNA damage markers, and inflammation increased significantly in the olfactory bulb of older mice. Lower NAD+ levels were also detected. Supplementation of NAD+ through NR in water improved longevity and partially enhanced olfaction in aged mice. Our studies provide mechanistic and biological insights into the olfaction decline during aging and highlight the role of NAD+ for preserving smelling function and general health.

M1/M4-Preferring Muscarinic Cholinergic Receptor Agonist Xanomeline Reverses Wake and Arousal Deficits in Nonpathologically Aged Mice.

Degeneration of the cholinergic basal forebrain is implicated in the development of cognitive deficits and sleep/wake architecture disturbances in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Indirect-acting muscarinic cholinergic receptor agonists, such as acetylcholinesterase inhibitors (AChEIs), remain the only FDA-approved treatments for the cognitive impairments observed in AD that target the cholinergic system. Novel direct-acting muscarinic cholinergic receptor agonists also improve cognitive performance in young and aged preclinical species and are currently under clinical development for AD. However, little is known about the effects of direct-acting muscarinic cholinergic receptor agonists on disruptions of sleep/wake architecture and arousal observed in nonpathologically aged rodents, nonhuman primates, and clinical populations. The purpose of the present study was to provide the first assessment of the effects of the direct-acting M1/M4-preferring muscarinic cholinergic receptor agonist xanomeline on sleep/wake architecture and arousal in young and nonpathologically aged mice, in comparison with the AChEI donepezil, when dosed in either the active or inactive phase of the circadian cycle. Xanomeline produced a robust reversal of both wake fragmentation and disruptions in arousal when dosed in the active phase of nonpathologically aged mice. In contrast, donepezil had no effect on either age-related wake fragmentation or arousal deficits when dosed during the active phase. When dosed in the inactive phase, both xanomeline and donepezil produced increases in wake and arousal and decreases in nonrapid eye movement sleep quality and quantity in nonpathologically aged mice. Collectively, these novel findings suggest that direct-acting muscarinic cholinergic agonists such as xanomeline may provide enhanced wakefulness and arousal in nonpathological aging, MCI, and AD patient populations.

A Novel Ketone-Supplemented Diet Improves Recognition Memory and Hippocampal Mitochondrial Efficiency in Healthy Adult Mice.

Mitochondrial dysfunction and cognitive impairment are common symptoms in many neurologic and psychiatric disorders, as well as nonpathological aging. Ketones have been suggested as therapeutic for their efficacy in epilepsy and other brain pathologies such as Alzheimer's disease and major depressive disorder. However, their effects on cognitive function in healthy individuals is less established. Here, we explored the mitochondrial and performative outcomes of a novel eight-week ketone-supplemented ketogenic (KETO) diet in healthy adult male and female mice. In a novel object recognition test, KETO mice spent more time with the novel, compared to familiar, object, indicating an improvement in recognition memory. High-resolution respirometry on permeabilized hippocampal tissue returned significant reductions in mitochondrial O2 consumption. No changes in ATP production were observed, yielding a significantly higher ATP:O2 ratio, a measure of mitochondrial efficiency. Together, these findings demonstrate the KETO diet improves hippocampal mitochondrial efficiency. They add to a growing body of evidence that suggests ketones and ketogenic diets are neuroprotective and metabolically and cognitively relevant, even in healthy adults. They also suggest that ketogenic lifestyle changes may be effective strategies for protecting against cognitive decline associated with aging and disease.

Intuitive assessment of spatial navigation beyond episodic memory: Feasibility and proof of concept in middle-aged and elderly individuals.

Deficits in spatial navigation in three-dimensional space are prevalent in various neurological disorders and are a sensitive cognitive marker for prodromal Alzheimer's disease, but are also associated with non-pathological aging. However, standard neuropsychological tests used in clinical settings lack ecological validity to adequately assess spatial navigation. Experimental paradigms, on the other hand, are often too difficult for seniors or patients with cognitive or motor impairments since most require operating a human interface device (HID) or use complex episodic memory tasks. Here, we introduce an intuitive navigation assessment, which is conceptualized using cognitive models of spatial navigation and designed to account for the limited technical experience and diverging impairments of elderly participants and neurological patients. The brief computer paradigm uses videos of hallways filmed with eye tracking glasses, without employing an episodic memory task or requiring participants to operate a HID. Proof of concept data from 34 healthy, middle-aged and elderly participants (56-78 years) provide evidence for the assessment's feasibility and construct validity as a navigation paradigm. Test performance showed normal distribution and was sensitive to age and education, which needs to be considered when investigating the assessment's psychometric properties in larger samples and clinical populations. Correlations of the navigation assessment with other neuropsychological tests confirmed its dependence on visuospatial skills rather than visual episodic memory, with age driving the association with working memory. The novel paradigm is suitable for a differentiated investigation of spatial navigation in elderly individuals and promising for experimental research in clinical settings.

Aging: working memory capacity and spatial strategies in a virtual orientation task.

Brain networks involved in working and spatial memory are closely intertwined, outlining a potential relation between these processes, which are also affected in non-pathological aging. Working memory is a pre-requisite for other complex cognitive processes. The main aim of this study is to explore how working memory capacity (WMC) can influence the asymmetrical decline in spatial orientation strategies in an older segment of population compared to young participants. Forty-eight older adults and twelve young students took part in the study. Working memory and spatial memory were assessed using the Change Localization Task and The Boxes Room Task, respectively. In The Boxes Room Task, two different configurations assessed the use of egocentric and allocentric reference frames. Results showed that older adults with better WMC outperformed those with lower WMC in several tasks. Independently of WMC capacity, older participants performed better in the allocentric condition of The Boxes Room. In addition, young participants outscored low WMC older participants, but did not differ from high WMC older adults. Overly, these findings support the important relationship between working memory capacity and spatial orientations abilities. Thus, basic cognitive mechanisms engaged in information processing could inform about other brain processes more complex in nature, like spatial orientation skills.

Overlap between Central and Peripheral Transcriptomes in Parkinson's Disease but Not Alzheimer's Disease.

Most neurodegenerative disorders take decades to develop, and their early detection is challenged by confounding non-pathological ageing processes. Therefore, the discovery of genes and molecular pathways in both peripheral and brain tissues that are highly predictive of disease evolution is necessary. To find genes that influence Alzheimer’s disease (AD) and Parkinson’s disease (PD) pathogenesis, human RNA-Seq transcriptomic data from Brodmann Area 9 (BA9) of the dorsolateral prefrontal cortex (DLPFC), whole blood (WB), and peripheral blood mononuclear cells (PBMC) were analysed using a combination of differential gene expression and a random forest-based machine learning algorithm. The results suggest that there is little overlap between PD and AD, and the AD brain signature is unique mainly compared to blood-based samples. Moreover, the AD-BA9 was characterised by changes in ‘nervous system development’ with Myocyte-specific enhancer factor 2C (Mef2C), encoding a transcription factor that induces microglia activation, a prominent feature. The peripheral AD transcriptome was associated with alterations in ‘viral process’, and FYN, which has been previously shown to link amyloid-beta and tau, was the prominent feature. However, in the absence of any overlap with the central transcriptome, it is unclear whether peripheral FYN levels reflect AD severity or progression. In PD, central and peripheral signatures are characterised by anomalies in ‘exocytosis’ and specific genes related to the SNARE complex, including Vesicle-associated membrane protein 2 (VAMP2), Syntaxin 1A (STX1A), and p21-activated kinase 1 (PAK1). This is consistent with our current understanding of the physiological role of alpha-synuclein and how alpha-synuclein oligomers compromise vesicle docking and neurotransmission. Overall, the results describe distinct disease-specific pathomechanisms, both within the brain and peripherally, for the two most common neurodegenerative disorders.

Impairments in Fear Extinction Memory and Basolateral Amygdala Plasticity in the TgF344-AD Rat Model of Alzheimer's Disease Are Distinct from Nonpathological Aging.

Fear-based disorders such as post-traumatic stress disorder (PTSD) steepen age-related cognitive decline and double the risk for developing Alzheimer’s disease (AD). Because of the seemingly hyperactive properties of fear memories, PTSD symptoms can worsen with age. Perturbations in the synaptic circuitry supporting fear memory extinction are key neural substrates of PTSD. The basolateral amygdala (BLA) is a medial temporal lobe structure that is critical in the encoding, consolidation, and retrieval of fear memories. As little is known about fear extinction memory and BLA synaptic dysfunction within the context of aging and AD, the goal of this study was to investigate how fear extinction memory deficits and basal amygdaloid nucleus (BA) synaptic dysfunction differentially associate in nonpathologic aging and AD in the TgF344AD (TgAD) rat model of AD. Young, middle-aged, and older-aged WT and TgAD rats were trained on a delay fear conditioning and extinction procedure before ex vivo extracellular field potential recording experiments in the BA. Relative to young WT rats, long-term extinction memory was impaired, and in general, was associated with a hyperexcitable BA and impaired LTP in TgAD rats at all ages. In contrast, long-term extinction memory was impaired in aged WT rats and was associated with impaired LTP but not BA hyperexcitability. Interestingly, the middle-aged TgAD rats showed intact short-term extinction and BA LTP, which is suggestive of a compensatory mechanism, whereas differential neural recruitment in older-aged WT rats may have facilitated short-term extinction. As such, associations between fear extinction memory and amygdala deficits in nonpathologic aging and AD are dissociable.

A Low‐carbohydrate, Ketogenic Diet Enhances Hippocampal Mitochondrial Bioenergetics and Efficiency

Mitochondrial dysfunction and cognitive impairment are common symptoms in many neurologic and psychiatric disorders, as well as in nonpathological aging. Ketones have been suggested as therapeutic for their relevance in epilepsy as well as other neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Here we explored whether a low‐carbohydrate, ketogenic diet (KD) alters recognition memory, hippocampal mitochondrial bioenergetics, and expression of proteins involved in mitochondrial dynamics. Mature‐to‐middle‐aged adult male and female mice were placed on a lard‐based KD supplemented with an exogenous ketone ester for eight weeks. Changes in behavioral recognition memory were measured in a two‐object novel object recognition test. Hippocampal mitochondrial physiology was assessed using high‐resolution respirometry to measure changes in oxygen flux, biochemical assays to quantify ATP production, and western blot to measure changes in Drp1 expression. Here we demonstrate that the KD reduces hippocampal oxygen consumption (p=0.013), but does not alter ATP production (p=0.42) or Drp1 expression (p=0.51). These results indicate an enhancement of mitochondrial coupling and efficiency independent of mitochondrial dynamics, as changes in oxygen flux occurred without changes in Drp1 expression. Together, these findings add to growing support for the use of ketones and KDs in pathological brain states in which mitochondrial function is compromised, especially within the hippocampus.

The association between head motion during functional magnetic resonance imaging and executive functioning in older adults

Minimizing head motion during functional magnetic resonance imaging (fMRI) is important for maintaining the integrity of neuroimaging data. While there are a variety of techniques to control for head motion, oftentimes, individuals with excessive in-scanner motion are removed from analyses. Movement in the scanner tends to increase with age; however, the cognitive profile of these “high-movers” in older adults has yet to be explored. This study aimed to assess the association between in-scanner head motion (i.e., number of “invalid scans” flagged as motion outliers) and cognitive functioning (e.g., executive functioning, processing speed, and verbal memory performance) in a sample of 282 healthy older adults. Spearman's Rank-Order correlations showed that a higher number of invalid scans was significantly associated with poorer performance on tasks of inhibition and cognitive flexibility and with older age. Since performance in these domains tend to decline as a part of the non-pathological aging process, these findings raise concerns regarding the potential systematic exclusion due to motion of older adults with lower executive functioning in neuroimaging samples. Future research should continue to explore prospective motion correction techniques to better ensure the collection of quality neuroimaging data without excluding informative participants from the sample.

Cingulo-opercular and frontoparietal control network connectivity and executive functioning in older adults.

Executive function is a cognitive domain that typically declines in non-pathological aging. Two cognitive control networks that are vulnerable to aging-the cingulo-opercular (CON) and fronto-parietal control (FPCN) networks-play a role in various aspects of executive functioning. However, it is unclear how communication within these networks at rest relates to executive function subcomponents in older adults. This study examines the associations between CON and FPCN connectivity and executive function performance in 274 older adults across working memory, inhibition, and set-shifting tasks. Average CON connectivity was associated with better working memory, inhibition, and set-shifting performance, while average FPCN connectivity was associated solely with working memory. CON region of interest analyses revealed significant connections with classical hub regions (i.e., anterior cingulate and anterior insula) for each task, language regions for verbal working memory, right hemisphere dominance for inhibitory control, and widespread network connections for set-shifting. FPCN region of interest analyses revealed largely right hemisphere fronto-parietal connections important for working memory and a few temporal lobe connections for set-shifting. These findings characterize differential brain-behavior relationships between cognitive control networks and executive function in aging. Future research should target these networks for intervention to potentially attenuate executive function decline in older adults.

TOMM40\u2018523\u2019 poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson\u2019s disease

The translocase of outer mitochondrial membrane 40 (TOMM40) ‘523’ polymorphism has previously been associated with age of Alzheimer’s disease onset and cognitive functioning in non-pathological ageing, but has not been explored as a candidate risk marker for cognitive decline in Parkinson’s disease (PD). Therefore, this longitudinal study investigated the role of the ‘523’ variant in cognitive decline in a patient cohort from the Parkinson’s Progression Markers Initiative. As such, a group of 368 people with PD were assessed annually for cognitive performance using multiple neuropsychological protocols, and were genotyped for the TOMM40 ‘523’ variant using whole-genome sequencing data. Covariate-adjusted generalised linear mixed models were utilised to examine the relationship between TOMM40 ‘523’ allele lengths and cognitive scores, while taking into account the APOE ε genotype. Cognitive scores declined over the 5-year study period and were lower in males than in females. When accounting for APOE ε4, the TOMM40 ‘523’ variant was not robustly associated with overall cognitive performance. However, in APOE ε3/ε3 carriers, who accounted for ~60% of the whole cohort, carriage of shorter ‘523’ alleles was associated with more severe cognitive decline in both sexes, while carriage of the longer alleles in females were associated with better preservation of global cognition and a number of cognitive sub-domains, and with a delay in progression to dementia. The findings indicate that when taken in conjunction with the APOE genotype, TOMM40 ‘523’ allele length is a significant independent determinant and marker for the trajectory of cognitive decline and risk of dementia in PD.

Spatial orientation tasks show moderate to high accuracy for the diagnosis of mild cognitive impairment: a systematic literature review.

Spatial disorientation has been observed in mild cognitive impairment (MCI) and is associated with a higher risk of progression to Alzheimer's disease (AD). However, there is no gold standard assessment for spatial orientation and paper-and-pencil tests lack ecological validity. Recently, there has been an increasing number of studies demonstrating the role of spatial disorientation as a cognitive marker of pathological decline, shedding new light on its importance for MCI. This systematic review aimed to investigate the accuracy of spatial orientation tasks for the diagnosis of MCI by comparison with cognitively healthy elderly. The search was conducted in the databases Medical Literature Analysis and Retrieval System Online (MEDLINE/PubMed), Web of Science, Scopus, Excerpta Medica Database (Embase), Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs) and Scientific Electronic Library Online (SciELO). Only original studies reporting spatial orientation assessment in MCI patients compared to a healthy control group were included. Studies were excluded if the MCI classification did not follow well described criteria and/or if accuracy results of spatial orientation assessment were not provided. Seven studies met the eligibility criteria, describing a variety of spatial orientation assessments including questionnaires, paper-and-pencil, office-based route learning, and computer-based and virtual reality tasks. Spatial orientation tasks demonstrated moderate to high accuracy in detecting elderly with MCI compared to cognitively healthy elderly, with areas under the curve (AUC) ranging from 0.77 to 0.99. However, important methodological issues were found in the selected studies which should be considered when interpreting results. Although the inclusion of spatial orientation assessments in MCI evaluations seems to have significant value, further studies are needed to clarify their true capacity to distinguish pathological from non-pathological aging.

Cholinergic Modulation of Glial Function During Aging and Chronic Neuroinflammation.

Aging is a complex biological process that increases the risk of age-related cognitive degenerative diseases such as dementia, including Alzheimer’s disease (AD), Lewy Body Dementia (LBD), and mild cognitive impairment (MCI). Even non-pathological aging of the brain can involve chronic oxidative and inflammatory stress, which disrupts the communication and balance between the brain and the immune system. There has been an increasingly strong connection found between chronic neuroinflammation and impaired memory, especially in AD. While microglia and astrocytes, the resident immune cells of the central nervous system (CNS), exerting beneficial effects during the acute inflammatory phase, during chronic neuroinflammation they can become more detrimental. Central cholinergic circuits are involved in maintaining normal cognitive function and regulating signaling within the entire cerebral cortex. While neuronal-glial cholinergic signaling is anti-inflammatory and anti-oxidative, central cholinergic neuronal degeneration is implicated in impaired learning, memory sleep regulation, and attention. Although there is evidence of cholinergic involvement in memory, fewer studies have linked the cholinergic anti-inflammatory and anti-oxidant pathways to memory processes during development, normal aging, and disease states. This review will summarize the current knowledge of cholinergic effects on microglia and astroglia, and their role in both anti-inflammatory and anti-oxidant mechanisms, concerning normal aging and chronic neuroinflammation. We provided details on how stimulation of α7 nicotinic acetylcholine (α7nACh) receptors can be neuroprotective by increasing amyloid-β phagocytosis, decreasing inflammation and reducing oxidative stress by promoting the nuclear factor erythroid 2-related factor 2 (Nrf2) pathways and decreasing the release of pro-inflammatory cytokines. There is also evidence for astroglial α7nACh receptor stimulation mediating anti-inflammatory and antioxidant effects by inhibiting the nuclear factor-κB (NF-κB) pathway and activating the Nrf2 pathway respectively. We conclude that targeting cholinergic glial interactions between neurons and glial cells via α7nACh receptors could regulate neuroinflammation and oxidative stress, relevant to the treatment of several neurodegenerative diseases.

How does the environment affect human ageing? An interdisciplinary review

The multifactorial process of ageing is one of the biggest biological and medical challenges of the 21st century with age-related conditions such as cardiovascular diseases, neurodegeneration and cancer being among the leading causes of death among industrialized countries. Rather than one single causative factor, a range of environmental, demographic, biological, behavioral and social factors determine the development and onset of age-related diseases (ARDs). While it remains a challenge to assess the cumulative effect of environmental influences on human ageing, growing evidence indicates that both ARDs and non-pathological ageing processes are driven by environmental influences. The present review takes a closer look at the different environmental factors including air, climate, water, soil, urban green, social and individual environments and their influence on common ARDs and other life-limiting pathologies. It is of major public health relevance, to understand the interactions between these factors to develop preventive strategies both at individual and societal level to support healthy ageing.