Aging may have an impact on the CA3 autoassociative network of the hippocampus, posited by computational models as supporting pattern completion. Twenty-five young (YAs) and 25 older adults (OAs) performed a spatial pattern completion task using a computerized navigational paradigm analogous to a rodent pattern completion task reliant on the CA3. Participants identified a previously seen goal location, and the availability of distal cues in the environment was manipulated such that 0, 2, or 4 cues were missing. Performance in both groups declined as a function of decreased cue availability. However, controlling for age differences in task performance during a pre-experimental baseline task, OAs performed equivalently to YAs when all cues were available, but worse than YAs as the number of cues decreased. These findings suggest spatial pattern completion may be impaired in OAs. We discuss these findings in the context of a growing body of literature suggesting age-related imbalances in pattern separation vs. pattern completion.
spatial pattern completion; navigation; aging; episodic memory; hippocampus
The dysfunction of cholinergic neurons is a typical hallmark in Alzheimer's disease (AD). Previous findings demonstrated that high density of cholinergic receptors is found in the thalamus and the cerebellum compared with the cerebral cortex and the hippocampus. We aimed at investigating whether activation of the cerebello-thalamo-cortical pathway by means of cerebellar theta burst stimulation (TBS) could modulate central cholinergic functions evaluated in vivo by using the neurophysiological determination of Short-Latency Afferent Inhibition (SLAI). We tested the SLAI circuit before and after administration of cerebellar continuous TBS (cTBS) in 12 AD patients and in 12 healthy age-matched control subjects (HS). We also investigated potential changes of intracortical circuits of the contralateral primary motor cortex (M1) by assessing short intracortical inhibition (SICI) and intracortical facilitation (ICF). SLAI was decreased in AD patients compared to HS. Cerebellar cTBS partially restored SLAI in AD patients at later inter-stimulus intervals (ISIs), but did not modify SLAI in HS. SICI and ICF did not differ in the two groups and were not modulated by cerebellar cTBS. These results demonstrate that cerebellar magnetic stimulation is likely to affect mechanisms of cortical cholinergic activity, suggesting that the cerebellum may have a direct influence on the cholinergic dysfunction in AD.
transcranial magnetic stimulation; cortical plasticity; cholinergic; cerebellum; Alzheimer's disease
Healthy young adults use different strategies when navigating in a virtual maze. Spatial strategies involve using environmental landmarks while response strategies involve executing a series of movements from specific stimuli. Neuroimaging studies previously confirmed that people who use spatial strategies show increased activity and gray matter in the hippocampus, while those who use response strategies show increased activity and gray matter in caudate nucleus (Iaria et al., 2003; Bohbot et al., 2007). A growing number of studies report that cognitive decline that occurs with normal aging is correlated with a decrease in volume of the hippocampus. Here, we used voxel-based morphometry (VBM) to examine whether spatial strategies in aging are correlated with greater gray matter in the hippocampus, as found in our previous study with healthy young participants. Forty-five healthy older adults were tested on a virtual navigation task that allows spatial and response strategies. All participants learn the task to criterion after which a special “probe” trial that assesses spatial and response strategies is given. Results show that spontaneous spatial memory strategies, and not performance on the navigation task, positively correlate with gray matter in the hippocampus. Since numerous studies have shown that a decrease in the volume of the hippocampus correlates with cognitive deficits during normal aging and increases the risks of ensuing dementia, the current results suggest that older people who use their spatial memory strategies in their everyday lives may have increased gray matter in the hippocampus and enhance their probability of healthy and successful aging.
aging; radial maze; spatial memory; hippocampus; navigation
Accurate ante mortem diagnosis in frontotemporal lobar degeneration (FTLD) is crucial to the development and implementation of etiology-based therapies. Several neurodegenerative disease-associated proteins, including the major protein constituents of inclusions in Alzheimer's disease (AD) associated with amyloid-beta (Aβ1−42) plaque and tau neurofibrillary tangle pathology, can be measured in cerebrospinal fluid (CSF) for diagnostic applications. Comparative studies using autopsy-confirmed samples suggest that CSF total-tau (t-tau) and Aβ1−42 levels can accurately distinguish FTLD from AD, with a high t-tau to Aβ1−42 ratio diagnostic of AD; however, there is also an urgent need for FTLD-specific biomarkers. These analytes will require validation in large autopsy-confirmed cohorts and face challenges of standardization of within- and between-laboratory sources of error. In addition, CSF biomarkers with prognostic utility and longitudinal study of CSF biomarker levels over the course of disease are also needed. Current goals in the field include identification of analytes that are easily and reliably measured and can be used alone or in a multi-modal approach to provide an accurate prediction of underlying neuropathology for use in clinical trials of disease modifying treatments in FTLD. To achieve these goals it will be of the utmost importance to view neurodegenerative disease, including FTLD, as a clinicopathological entity, rather than exclusively a clinical syndrome.
cerebrospinal fluid; biomarker; tau; Aβ1−42; frontotemporal dementia; primary progressive aphasia; Alzheimer's disease
During aging, sensorimotor, cognitive and physical performance decline, but can improve by training and exercise indicating that age-related changes are treatable. Dancing is increasingly used as an intervention because it combines many diverse features making it a promising neuroplasticity-inducing tool. We here investigated the effects of a 6-month dance class (1 h/week) on a group of healthy elderly individuals compared to a matched control group (CG). We performed a broad assessment covering cognition, intelligence, attention, reaction time, motor, tactile, and postural performance, as well as subjective well-being and cardio-respiratory performance. After 6 months, in the CG no changes, or further degradation of performance was found. In the dance group, beneficial effects were found for dance-related parameters such as posture and reaction times, but also for cognitive, tactile, motor performance, and subjective well-being. These effects developed without alterations in the cardio-respiratory performance. Correlation of baseline performance with the improvement following intervention revealed that those individuals, who benefitted most from the intervention, were those who showed the lowest performance prior to the intervention. Our findings corroborate previous observations that dancing evokes widespread positive effects. The pre-post design used in the present study implies that the efficacy of dance is most likely not based on a selection bias of particularly gifted individuals. The lack of changes of cardio-respiratory fitness indicates that even moderate levels of physical activity can in combination with rich sensorimotor, cognitive, social, and emotional challenges act to ameliorate a wide spectrum of age-related decline.
enriched environment; dance therapy; VO2max; intervention; sensorimotor; cognition; balance; successful aging
Balance deteriorates with age, and may eventually lead to falling accidents which may threaten independent living. As Taekwondo contains various highly dynamic movement patterns, Taekwondo practice may sustain or improve balance. Therefore, in 24 middle-aged healthy volunteers (40–71 year) we investigated effects of age-adapted Taekwondo training of 1 h a week during 1 year on various balance parameters, such as: motor orientation ability (primary outcome measure), postural and static balance test, single leg stance, one leg hop test, and a questionnaire. Motor orientation ability significantly increased in favor of the antero-posterior direction with a difference of 0.62° toward anterior compared to pre-training measurement, when participants corrected the tilted platform rather toward the posterior direction; female gender being an independent outcome predictor. On postural balance measurements sway path improved in all 19 participants, with a median of 9.3 mm/s (range 0.71–45.86), and sway area in 15 participants with 4.2 mm2/s (range 17.39–1.22). Static balance improved with an average of 5.34 s for the right leg, and with almost 4 s for the left. Median single leg stance duration increased in 17 participants with 5 s (range 1–16), and in 13 participants with 8 s (range 1–18). The average one leg hop test distance increased (not statistically significant) with 9.5 cm. The questionnaire reported a better “ability to maintain balance” in 16. In conclusion, our data suggest that age-adapted Taekwondo training improves various aspects of balance control in healthy people over the age of 40.
hard martial arts; Taekwondo; senior citizens; static balance; dynamic balance
This short review will summarize the current knowledge on the uptake, storage, and export of copper ions by astrocytes and will address the potential roles of astrocytes in copper homeostasis in the normal and diseased brain. Astrocytes in culture efficiently accumulate copper by processes that include both the copper transporter Ctr1 and Ctr1-independent mechanisms. Exposure of astrocytes to copper induces an increase in cellular glutathione (GSH) content as well as synthesis of metallothioneins, suggesting that excess of copper is stored as complex with GSH and in metallothioneins. Furthermore, exposure of astrocytes to copper accelerates the release of GSH and glycolytically generated lactate. Astrocytes are able to export copper and express the Menkes protein ATP7A. This protein undergoes reversible, copper-dependent trafficking between the trans-Golgi network and vesicular structures. The ability of astrocytes to efficiently take up, store and export copper suggests that astrocytes play a key role in the supply of neurons with copper and that astrocytes should be considered as target for therapeutic interventions that aim to correct disturbances in brain copper homeostasis.
ATP7A; astroglia; copper export; Ctr1; metallothioneins; oxidative stress; toxicity; transport
Copper, iron, and zinc are just three of the main biometals critical for correct functioning of the central nervous system (CNS). They have diverse roles in many functional processes including but not limited to enzyme catalysis, protein stabilization, and energy production. The range of metal concentrations within the body is tightly regulated and when the balance is perturbed, debilitating effects ensue. Homeostasis of brain biometals is mainly controlled by various metal transporters and metal sequestering proteins. The biological roles of biometals are vastly reviewed in the literature with a large focus on the connection to neurological conditions associated with ageing. Biometals are also implicated in a variety of debilitating inherited childhood disorders, some of which arise soon following birth or as the child progresses into early adulthood. This review acts to highlight what we know about biometals in childhood neurological disorders such as Wilson's disease (WD), Menkes disease (MD), neuronal ceroid lipofuscinoses (NCLs), and neurodegeneration with brain iron accumulation (NBIA). Also discussed are some of the animal models available to determine the pathological mechanisms in these childhood disorders, which we hope will aid in our understanding of the role of biometals in disease and in attaining possible therapeutics in the future.
metals; neurodegeneration; childhood; copper; iron; zinc
Cognitive training and aerobic training are known to improve cognitive functions. To examine the separate and combined effects of such training on cognitive performance, four groups of healthy older adults embarked on a 4 months cognitive and/or mild aerobic training. A first group [n = 33, mean age = 80 (66–90)] engaged in cognitive training, a second [n = 29, mean age = 81 (65–89)] in mild aerobic training, a third [n = 29, mean age = 79 (70–93)] in the combination of both, and a fourth [n = 31, mean age = 79 (71–92)] control group engaged in book-reading activity. The outcome was a well-validated multi-domain computerized cognitive evaluation for older adults. The results indicate that, when compared to older adults who did not engage in cognitive training (the mild aerobic and control groups) older adults who engaged in cognitive training (separate or combined training groups) showed significant improvement in cognitive performance on Hand-Eye Coordination, Global Visual Memory (GVM; working memory and long-term memory), Speed of Information Processing, Visual Scanning, and Naming. Indeed, individuals who did not engage in cognitive training showed no such improvements. Those results suggest that cognitive training is effective in improving cognitive performance and that it (and not mild aerobic training) is driving the improvement in the combined condition. Results are discussed in terms of the special circumstances of aerobic and cognitive training for older adults who are above 80 years of age.
older adults; cognitive training; cognitive function; physical activity; CogniFit; brain plasticity
Objective: Our goal was to evaluate the association of APOE with amyloid deposition, cerebrospinal fluid levels (CSF) of Aβ, tau, and p-tau, brain atrophy, cognition and cognitive complaints in E-MCI patients and cognitively healthy older adults (HC) in the ADNI-2 cohort.
Methods: Two-hundred and nine E-MCI and 123 HC participants from the ADNI-2 cohort were included. We evaluated the impact of diagnostic status (E-MCI vs. HC) and APOE ε4 status (ε4 positive vs. ε4 negative) on cortical amyloid deposition (AV-45/Florbetapir SUVR PET scans), brain atrophy (structural MRI scans processed using voxel-based morphometry and Freesurfer version 5.1), CSF levels of Aβ, tau, and p-tau, and cognitive performance and complaints.
Results: E-MCI participants showed significantly impaired cognition, higher levels of cognitive complaints, greater levels of tau and p-tau, and subcortical and cortical atrophy relative to HC participants (p < 0.05). Cortical amyloid deposition and CSF levels of Aβ were significantly associated with APOE ε4 status but not E-MCI diagnosis, with ε4 positive participants showing more amyloid deposition and lower levels of CSF Aβ than ε4 negative participants. Other effects of APOE ε4 status on cognition and CSF tau levels were also observed.
APOE ε4 status is associated with amyloid accumulation and lower CSF Aβ, as well as increased CSF tau levels in early prodromal stages of AD (E-MCI) and HC. Alternatively, neurodegeneration, cognitive impairment, and increased complaints are primarily associated with a diagnosis of E-MCI. These findings underscore the importance of considering APOE genotype when evaluating biomarkers in early stages of disease.
apolipoprotein E (APOE); early mild cognitive impairment (E-MCI); Florbetapir/AV-45/Amyvid; positron emission tomography (PET); magnetic resonance imaging (MRI); cerebrospinal fluid (CSF); Alzheimer's disease neuroimaging initiative (ADNI)
Participants with the gene expansion for Huntington disease (HD) but not yet diagnosed were evaluated annually. Unidimensional diagnosis (UD) was a motor diagnosis defined as a diagnostic confidence level (DCL) of 4 (unequivocal motor signs, ≥99% confidence) on the standardized motor exam of the Unified Huntington Disease Rating Scale (UHDRS). Multidimensional diagnosis (MD) was defined as answering yes on Question 80 (Q80) of the UHDRS, ≥99% confidence of manifest HD based on the entire UHDRS. Motor, cognitive, and behavioral measures of phenotype at first diagnosis were compared by t-tests between participants diagnosed via motor exam (UD) and those diagnosed via multidimensional input (MD). Cluster analysis identified clusters based on UHDRS domains.186 participants received a diagnosis of HD during a maximum of 6.4 years of follow-up. In 108 (58.1%) the diagnosis by MD and UD occurred simultaneously, while in 69 (37.1%) the diagnosis by MD occurred prior to UD. Participants who were diagnosed by MD prior to UD were less impaired on motor (12.2 ± 6.7 vs. 22.4 ± 9.3, p < 0.0001), and cognitive (290.7 ± 56.2 vs. 258.0 ± 53.7, p = 0.0002), but not behavioral measures (16.3 ± 21.2 vs. 18.6 ± 22.1, p = 0.49) when compared with those diagnosed simultaneously. Cluster analysis identified three clusters that represented primarily cognitively impaired, behaviorally impaired, and cognitively preserved phenotypes. A multidimensional method results in an earlier diagnosis with less motor and cognitive impairment than a motor diagnosis. Findings have implications for designing preventive trials and providing clinical care in prodromal HD.
Huntington's disease; trinucleotide repeat diseases; cohort studies; natural history studies; outcome research
Background: Alzheimer's disease (AD) differs from other forms of dementia in its relation to amyloid beta peptide (Aβ42). Using a cell culture model we previously identified annexin A5, a Ca2+, and phospholipid binding protein, as an AD biomarker. Plasma level of annexin A5 was significantly higher in AD patients compared to that in a control group. On the other hand, AD has been identified to share a number of clinical and pathological features with Dementia with Lewy bodies (DLB). The present study was done to examine whether or not plasma annexin A5 is a specific marker for AD, when being compared with the levels of DLB patients. As Apolipoprotein E (ApoE) gene subtype ε4 (ApoE-ε4) has been noticed as the probable genetic factor for AD, we also examined and compared ApoE genotype in both AD and DLB.
Methods: Blood samples were obtained from 150 patients with AD (aged 77.6 ± 6.5 years), 50 patients of DLB (79.4 ± 5.0) and 279 community-dwelling healthy elderly individuals of comparable age and sex (75.6 ± 8.1). All AD patients met NINCDS-ADRDA criteria and all DLB patients were diagnosed as probable DLB according to the latest consensus diagnostic criteria. Quantification was done using the Chemiluminescent Enzyme Immunoassay (CLEIA) Technique (SphereLight assay) using the monoclonal antibodies against annexin A5. DNA genotyping of ApoE was performed by distinguishing unique combinations of Hha1 fragments of PCR-amplified genomic DNA products.
Results: The plasma level of annexin A5 was significantly higher in AD patients than in the healthy individuals (control) (P < 0.0001). The plasma annexin A5 level was also significantly higher in DLB patients than in the control group (P < 0.0001). From the ROC curves with plasma annexin A5 concentrations, the mean areas under the curve were 0.863 and 0.838 for the AD/control and DLB/control, respectively. The rate of ApoE4 carrier status and the frequency of the ε4 allele were significantly higher in AD or DLB than in control and there was no significant difference between AD and DLB.
Conclusions: These results suggest that both annexin A5 and ApoE4 are common markers for AD and DLB.
plasma biomarker; Alzheimer's disease; dementia with lewy bodies; annexin A5; Ca2+-stress; ROC curve; ApoE
Sirtuins are highly conserved NAD+-dependent enzymes that were shown to have beneficial effects against age-related diseases. Alzheimer's Disease (AD) is the most common neurodegenerative disorder associated with aging and the effects of sirtuins on AD have been investigated using different mouse and cell culture models. In most of these studies, it has been found that the overexpression of SIRT1 has protective effects against the AD phenotype. Therefore, designing therapeutics based on SIRT1 activity might be important to investigate treatment methods for this disease. In this review, we summarize the recent research regarding the functions of sirtuins and their potential roles in designing therapeutics for AD.
sirtuins; aging; Alzheimer's disease; neurodegeneration; genetic models
Vascular cognitive impairment (VCI) [vascular cognitive disorder (VCD), vascular dementia] describes a continuum of cognitive disorders ranging from mild cognitive impairment (MCI) to dementia, in which vascular brain injury involving regions important for memory, cognition and behavior plays an important role. Clinical diagnostic criteria show moderate sensitivity (ca 50%) and variable specificity (range 64–98%). In Western clinical series, VaD is suggested in 8–10% of cognitively impaired elderly subjects. Its prevalence in autopsy series varies from 0.03 to 58%, with means of 8 to 15% (in Japan 22–35%). Major types of sporadic VaD are multi-infarct encephalopathy, small vessel and strategic infarct type dementias, subcortical arteriosclerotic leukoencephalopathy (SAE) (Binswanger), multilacunar state, mixed cortico-subcortical type, granular cortical atrophy (rare), postischemic encephalopathy, and a mixture of cerebrovascular lesions (CVLs). They result from systemic, cardiac and local large or small vessel disease (SVD); their pathogenesis is multifactorial. Hereditary forms of VaD caused by gene mutations are rare. Cognitive decline is commonly associated with widespread small ischemic vascular lesions involving subcortical brain areas (basal ganglia and hemispheral white matter). The lesions affect neuronal networks involved in cognition, memory, and behavior (thalamo-cortical, striato-subfrontal, cortico-subcortical, limbic systems). CVLs often coexist with Alzheimer-type lesions and other pathologies; 25–80% of elderly demented show mixed pathologies. The lesion pattern of “pure” VaD differs from that in mixed dementia (AD + CVLs) suggesting different pathogenesis of both phenotypes. Minor CVLs, except for severe amyloid angiopathy, appear not essential for cognitive impairment in full-blown AD, while both mild AD-type pathology and SVD may interact synergistically in promoting dementia. However, in a large percentage of non-demented elderly individuals, both AD-related and vascular brain pathologies have been reported. Despite recent suggestions for staging and grading CVLs in specific brain areas, due to the high variability of CVLs associated with cognitive impairment, no validated neuropathological criteria are currently available for VaD and mixed dementia. Further clinico-pathological studies and harmonization of neuropathological procedures are needed to validate the diagnostic criteria for VaD and mixed dementia in order to clarify the impact of CVLs and other coexistent pathologies on cognitive impairment as a basis for further successful therapeutic options.
vascular dementia; vascular cognitive impairment; cerebral infarcts; large and small vessel disease; subcortical vascular lesions; neuropathology; pathogenic factors
Considerable evidence implicates hypoxia and vascular inflammation in Alzheimer's disease (AD). Thrombin, a multifunctional inflammatory mediator, is demonstrable in the brains of AD patients both in the vessel walls and senile plaques. Hypoxia-inducible factor 1α (HIF-1α), a key regulator of the cellular response to hypoxia, is also upregulated in the vasculature of human AD brains. The objective of this study is to investigate inflammatory protein expression in the cerebrovasculature of transgenic AD mice and to explore the role of thrombin as a mediator of cerebrovascular inflammation and oxidative stress in AD and in hypoxia-induced changes in brain endothelial cells. Immunofluorescent analysis of the cerebrovasculature in AD mice demonstrates significant (p < 0.01–0.001) increases in thrombin, HIF-1α, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases (MMPs), and reactive oxygen species (ROS) compared to controls. Administration of the thrombin inhibitor dabigatran (100 mg/kg) to AD mice for 34 weeks significantly decreases expression of inflammatory proteins and ROS. Exposure of cultured brain endothelial cells to hypoxia for 6 h causes an upregulation of thrombin, HIF-1α, MCP-1, IL-6, and MMP2 and ROS. Treatment of endothelial cells with the dabigatran (1 nM) reduces ROS generation and inflammatory protein expression (p < 0.01–0.001). The data demonstrate that inhibition of thrombin in culture blocks the increase in inflammatory protein expression and ROS generation evoked by hypoxia. Also, administration of dabigatran to transgenic AD mice diminishes ROS levels in brain and reduces cerebrovascular expression of inflammatory proteins. Taken together, these results suggest that inhibiting thrombin generation could have therapeutic value in AD and other disorders where hypoxia, inflammation, and oxidative stress are involved.
Alzheimer's disease; thrombin; hypoxia; neuroinflammation; endothelial cells; dabigatran
The model species, Caenorhabditis elegans, has been used as a tool to probe for mechanisms underlying numerous neurodegenerative diseases. This use has been exploited to study neurodegeneration induced by metals. The allure of the nematode comes from the ease of genetic manipulation, the ability to fluorescently label neuronal subtypes, and the relative simplicity of the nervous system. Notably, C. elegans have approximately 60–80% of human genes and contain genes involved in metal homeostasis and transport, allowing for the study of metal-induced degeneration in the nematode. This review discusses methods to assess degeneration as well as outlines techniques for genetic manipulation and presents a comprehensive survey of the existing literature on metal-induced degeneration studies in the worm.
neurodegeneration; behavior; metals; C. elegans; neurotransmitters
Working memory is a cognitive process that is particularly vulnerable to decline with age. The current study sought to evaluate the efficacy of a working memory training scheme in improving memory in a group of older adults. A 5-week online training scheme was designed to provide training in the main components of Baddeley’s (2000) working memory model, namely auditory and visuospatial short-term and working memory. A group of older adults aged between 64 and 79 were randomly assigned to a trainee (n = 19) or control (n = 17) group, with trainees engaging in the adaptive training scheme and controls engaging in a non-adaptive version of the program. Before and after training and at 3- and 6-month follow-up sessions, trainees and controls were asked to complete measures of short-term and working memory, long-term episodic memory, subjective ratings of memory, and attention and achievement of goals set at the beginning of training. The results provided evidence of an expansion of auditory short-term memory span, which was maintained 6 months later, and transfer to long-term episodic memory but no evidence of improvement in working memory capacity per se. A serendipitous and intriguing finding of a relationship between time spent training, psychological stress, and training gains provided further insight into individual differences in training gains in older adults.
working memory; aging; cognitive training; stress; cognitive decline
Early identification of persons at risk for cognitive decline in aging is critical to optimizing treatment to delay or avoid a clinical diagnosis of mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD). To accomplish early identification, it is essential that trajectories of cognitive change be characterized and associations with established biomarkers of MCI and AD be examined during the phase in which older persons are considered cognitively healthy. Here we examined the association of rate of cognitive decline in the years leading up to structural magnetic resonance imaging with an established biomarker, hippocampal volume. The sample comprised 211 participants of the Rush Memory and Aging Project who had an average of 5.5 years of cognitive data prior to structural scanning. Results showed that there was significant variability in the trajectories of cognitive change prior to imaging and that faster cognitive decline was associated with smaller hippocampal volumes. Domain-specific analyses suggested that this association was primarily driven by decline in working memory. The results emphasize the importance of closely examining cognitive change and its association with brain structure during the years in which older persons are considered cognitively healthy.
neuroimaging; macrostructure; hippocampal volume; aging; dementia; Alzheimer's disease; mild cognitive impairment; Rush Memory and Aging Project
The FOXO family of transcription factors is central to the regulation of organismal longevity and cellular survival. Several studies have indicated that FOXO factors lie at the center of a complex network of upstream pathways, cofactors and downstream targets (FOXO-interaction networks), which may have developmental and post-developmental roles in the regulation of chronic-stress response in normal and diseased cells. Noticeably, FOXO factors are important for the regulation of proteotoxicity and neuron survival in several models of neurodegenerative disease, suggesting that FOXO-interaction networks may have therapeutic potential. However, the status of FOXO-interaction networks in neurodegenerative disease remains largely unknown. Systems modeling is anticipated to provide a comprehensive assessment of this question. In particular, interrogating the context-dependent variability of FOXO-interaction networks could predict the clinical potential of cellular-stress response genes and aging regulators for tackling brain and peripheral pathology in neurodegenerative disease. Using published transcriptomic data obtained from murine models of Huntington's disease (HD) and post-mortem brains, blood samples and induced-pluripotent-stem cells from HD carriers as a case example, this review briefly highlights how the biological status and clinical potential of FOXO-interaction networks for HD may be decoded by developing network and entropy based feature selection across heterogeneous datasets.
Huntington's disease; cellular-stress response; FOXO network; clinical potential; gene prioritization; system-level approach; entropy
Manganese (Mn) is an essential metal and has important physiological functions for human health. However, exposure to excess levels of Mn in occupational settings or from environmental sources has been associated with a neurological syndrome comprising cognitive deficits, neuropsychological abnormalities and parkinsonism. Historically, studies on the effects of Mn in humans and experimental animals have been concerned with effects on the basal ganglia and the dopaminergic system as it relates to movement abnormalities. However, emerging studies are beginning to provide significant evidence of Mn effects on cortical structures and cognitive function at lower levels than previously recognized. This review advances new knowledge of putative mechanisms by which exposure to excess levels of Mn alters neurobiological systems and produces neurological deficits not only in the basal ganglia but also in the cerebral cortex. The emerging evidence suggests that working memory is significantly affected by chronic Mn exposure and this may be mediated by alterations in brain structures associated with the working memory network including the caudate nucleus in the striatum, frontal cortex and parietal cortex. Dysregulation of the dopaminergic system may play an important role in both the movement abnormalities as well as the neuropsychiatric and cognitive function deficits that have been described in humans and non-human primates exposed to Mn.
manganese; neurotoxicity; Parkinson's disease; dopamine; motor function; cognitive function; working memory
Iron is essential for life, but excess iron can be toxic. As a potent free radical creator, iron generates hydroxyl radicals leading to significant oxidative stress. Since iron is not excreted from the body, it accumulates with age in tissues, including the retina, predisposing to age-related oxidative insult. Both hereditary and acquired retinal diseases are associated with increased iron levels. For example, retinal degenerations have been found in hereditary iron overload disorders, like aceruloplasminemia, Friedreich's ataxia, and pantothenate kinase-associated neurodegeneration. Similarly, mice with targeted mutation of the iron exporter ceruloplasmin and its homolog hephaestin showed age-related retinal iron accumulation and retinal degeneration with features resembling human age-related macular degeneration (AMD). Post mortem AMD eyes have increased levels of iron in retina compared to age-matched healthy donors. Iron accumulation in AMD is likely to result, in part, from inflammation, hypoxia, and oxidative stress, all of which can cause iron dysregulation. Fortunately, it has been demonstrated by in vitro and in vivo studies that iron in the retinal pigment epithelium (RPE) and retina is chelatable. Iron chelation protects photoreceptors and retinal pigment epithelial cells (RPE) in a variety of mouse models. This has therapeutic potential for diminishing iron-induced oxidative damage to prevent or treat AMD.
iron; retina; age-related macular degeneration (AMD); chelator; oxidative stress; ferroportin; ceruloplasmin; hephaestin
Insulin-like growth factor-1 (IGF-1) is an important anabolic hormone that decreases with age. In the past two decades, extensive research has determined that the reduction in IGF-1 is an important component of the age-related decline in cognitive function in multiple species including humans. Deficiency in circulating IGF-1 results in impairment in processing speed and deficiencies in both spatial and working memory. Replacement of IGF-1 or factors that increase IGF-1 to old animals and humans reverses many of these cognitive deficits. Despite the overwhelming evidence for IGF-1 as an important neurotrophic agent, the specific mechanisms through which IGF-1 acts have remained elusive. Recent evidence indicates that IGF-1 is both produced by and has important actions on the cerebrovasculature as well as neurons and glia. Nevertheless, the specific regulation and actions of brain- and vascular-derived IGF-1 is poorly understood. The diverse effects of IGF-1 discovered thus far reveal a complex endocrine and paracrine system essential for integrating many of the functions necessary for brain health. Identification of the mechanisms of IGF-1 actions will undoubtedly provide critical insight into regulation of brain function in general and the causes of cognitive decline with age.
aging; cognitive decline; IGF-1; vasculature