MicroRNAs in age-related diseases

Aging is a complex process that is linked to an increased incidence of major diseases such as cardiovascular and neurodegenerative disease, but also cancer and immune disorders. MicroRNAs (miRNAs) are small non-coding RNAs, which post-transcriptionally control gene expression by inhibiting translation or inducing degradation of targeted mRNAs. MiRNAs target up to hundreds of mRNAs, thereby modulating gene expression patterns. Many miRNAs appear to be dysregulated during cellular senescence, aging and disease. However, only few miRNAs have been so far linked to age-related changes in cellular and organ functions. The present article will discuss these findings, specifically focusing on the cardiovascular and neurological systems

Normal aging and Alzheimer's disease : hippocampal and episodic memory differences

Alzheimer’s Disease (AD) and normal aging (NA) are characterized by structural brain changes as well as cognitive changes that appear over the lifespan. The hippocampus is an area susceptible to early atrophy in both AD and NA; however the differential causes of atrophy are not entirely clear. Hippocampal volume loss in AD is attributed to neuronal death due to underlying pathology. AD often is diagnosed years after the onset of pathology and subsequent atrophy. NA is a continuation of cognitive decline that does not become dementia. Episodic memory (EM) is processed within the hippocampus and is one of the first systems to show deficits in conjunction with both patterns of aging. This review focuses on hippocampal volume loss and EM decline in NA and AD.Communication Sciences and Disorder

Functional Magnetic Resonance Imaging of Semantic Memory as a Presymptomatic Biomarker of Alzheimer’s Disease Risk

Extensive research efforts have been directed toward strategies for predicting risk of developing Alzheimer\u27s disease (AD) prior to the appearance of observable symptoms. Existing approaches for early detection of AD vary in terms of their efficacy, invasiveness, and ease of implementation. Several non-invasive magnetic resonance imaging strategies have been developed for predicting decline in cognitively healthy older adults. This review will survey a number of studies, beginning with the development of a famous name discrimination task used to identify neural regions that participate in semantic memory retrieval and to test predictions of several key theories of the role of the hippocampus in memory. This task has revealed medial temporal and neocortical contributions to recent and remote memory retrieval, and it has been used to demonstrate compensatory neural recruitment in older adults, apolipoprotein E ε4 carriers, and amnestic mild cognitive impairment patients. Recently, we have also found that the famous name discrimination task provides predictive value for forecasting episodic memory decline among asymptomatic older adults. Other studies investigating the predictive value of semantic memory tasks will also be presented. We suggest several advantages associated with the use of semantic processing tasks, particularly those based on person identification, in comparison to episodic memory tasks to study AD risk. Future directions for research and potential clinical uses of semantic memory paradigms are also discussed. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease

Predicting Cognitive Decline in Older Adults Through Multi-Voxel Pattern Analysis

Alzheimer\u27s disease (AD) is a progressive neurodegenerative disorder that is associated with cognitive and structural decline beyond what is seen in normal, healthy aging. Functional magnetic resonance imaging (fMRI) research indicates that prior to the onset of measureable cognitive impairment, individuals at-risk for AD demonstrate different patterns of neural activation than individuals at lower risk. Thus, differences in task-activated fMRI may be beneficial in predicting cognitive decline at a pre-symptomatic stage. The present study utilizes multi-voxel pattern analysis (MVPA) of baseline fMRI task-related activation to predict cognitive decline, with the hypothesis that famous and non-famous name task activation will discriminate older adults who go on to experience cognitive decline from those who do not. Ninety-nine cognitively intact older adults underwent neuropsychological testing and a semantic memory fMRI task (famous name discrimination). After follow-up neuropsychological testing 18-months later, participants were grouped as Stable (n = 65) or Declining (n = 34) based on \u3e 1.0 SD decline in performance on cognitive measures. MVPA classification accuracy was 90% for stimulus type (famous and non-famous names), thereby supporting the general approach. Mean MVPA classification accuracy for famous and non-famous names was 83% for both the Stable and Declining groups. Finally, MVPA produced greater than chance classification accuracy of participant groups for both famous name activation (56%) and non-famous name activation (55%) as determined via binomial distribution. The results of the current study suggest that MVPA possesses potential in predicting cognitive decline in older adults

The proteostasis network and its decline in ageing

Ageing is a major risk factor for the development of many diseases, prominently including neurodegenerative disorders such as Alzheimer disease and Parkinson disease. A hallmark of many age-related diseases is the dysfunction in protein homeostasis (proteostasis), leading to the accumulation of protein aggregates. In healthy cells, a complex proteostasis network, comprising molecular chaperones and proteolytic machineries and their regulators, operates to ensure the maintenance of proteostasis. These factors coordinate protein synthesis with polypeptide folding, the conservation of protein conformation and protein degradation. However, sustaining proteome balance is a challenging task in the face of various external and endogenous stresses that accumulate during ageing. These stresses lead to the decline of proteostasis network capacity and proteome integrity. The resulting accumulation of misfolded and aggregated proteins affects, in particular, postmitotic cell types such as neurons, manifesting in disease. Recent analyses of proteome-wide changes that occur during ageing inform strategies to improve proteostasis. The possibilities of pharmacological augmentation of the capacity of proteostasis networks hold great promise for delaying the onset of age-related pathologies associated with proteome deterioration and for extending healthspan

Mid age APOE ε4 carriers show memory-related functional differences and disrupted structure-function relationships in hippocampal regions

Carriers of the APOE e4 allele are at higher risk of age-related cognitive decline and Alzheimer's disease (AD). The underlying neural mechanisms are uncertain, but genotype differences in medial temporal lobe (MTL) functional activity and structure at mid-age might contribute. We tested 16 non-e4 and 16 e4 carriers (aged 45-55) on a subsequent memory task in conjunction with MRI to assess how hippocampal volume (from T1 structural) and microstructure (neurite orientation-dispersion, from NODDI) differs by genotype and in relation to memory encoding. No previous study has investigated APOE effects on hippocampal microstructure using NODDI. Recall performance did not differ by genotype. A genotype by condition interaction in left parahippocampus indicated that in e4 carriers activity did not differentiate subsequently remembered from forgotten words. Hippocampal volumes and microstructure also did not differ by genotype but hippocampal volumes correlated positively with recognition performance in non-e4 carriers only. Similarly, greater hippocampal neurite orientation-dispersion was linked to better recall but only in non-e4s. Thus, we suggest that mid-age e4 carriers show a breakdown of normal MTL activation and structure-performance relationships. This could reflect an inability to utilise compensatory mechanisms, and contribute to higher risk of cognitive decline and AD in later life

Neurodegeneration: Paying It Off with Sleep

SummaryA new study in fruit flies suggests modulation of neural activity links sleep and Alzheimer’s disease. Both sleep loss and amyloid beta increase neural excitability, which reinforces the accumulation of amyloid beta and shortens lifespan

Fact, Fiction, or Evolution: Mechanism Hypothesis of Alzheimer’s Disease

The metabolism hypothesis of Alzheimer’s disease (AD) was first proposed in 1975. In normal aging and very mild AD, the cerebral metabolic rate for oxygen (CMRO2) and cerebral blood flow (CBF) remained approximately constant, but the metabolism of glucose (CMRglu) declined markedly. This decline in CMRglu identified a specific and primary metabolic defect that triggered downstream cellular cascades evolving into AD and its characteristic neuropathological lesions. These findings led research about AD into the role of insulin resistance that foresaw modern trials of insulin for AD treatment. The metabolism hypothesis evolved over subsequent decades with improved in-vivo measurement of metabolic parameters and AD biomarkers in humans. A more recent model highlights the interrelationships between the default mode network (DMN) and biomarkers such as CMRglu, amyloid, and tau. In other words, metabolic conditions related to sustained cortical activity during aging throughout the lifetime are conducive to the deposition of amyloid. This activity is thought to underlie the “autobiographical self.” These ideas and findings motivate aging and AD-research focus on the biochemistry and cell biology of cerebral metabolism

Nutrition as a Modifiable Risk Factor for Cognitive Decline: Associated Cognitive and Physical Health Changes

Dementia is defined as gradual, progressive loss of cognitive functioning, greater than what is expected of normal aging, resulting in functional impairment. There are several types of dementia clinical syndromes that are accompanied by unique patterns of cognitive dysfunction and neuropathological changes. Alzheimer’s disease (AD) is the most common type of clinical dementia syndrome, accounting for approximately 60-70% of cases. Neuropathological mechanisms associated with AD include the disruption of the cholinergic system, accumulation of amyloid-beta plaques and hyperphosphorylated tau, as well as vascular pathology. Vascular pathology complicates the characterization of clinical and neuropathic changes in AD, as there becomes significant overlap with vascular dementia clinical presentation and pathology. Furthermore, many people with dementia have “mixed dementia,” or brain changes associated with more than one cause of dementia. This may contribute to the difficulty establishing effective pharmacological interventions to reverse or prevent future neurodegeneration. As a result, research examining modifiable risk factors to prevent neuropathological changes associated with dementia, including AD, has become of interest. Modifiable risk factors include physical activity, sleep, alcohol and tobacco use, and nutrition. Diet has been proposed to reduce risk of AD via neuroinflammatory mechanisms, oxidative stress, and by reducing risk for other comorbid medical conditions (e.g., vascular disease, diabetes, hypertension). There is limited research in the examination of the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet and cognition, longitudinally, in a middle-aged sample, as well as the potential moderating effect of APOE genotype, of which the e4 allele confers increased risk for AD. The current proposal provides a literature review of AD, including cognitive and neuropathological changes, as well as AD vascular factors, and diet as a modifiable risk factor. The proposed study aimed to examine the longitudinal effects of nonmodifiable risk factors (age, gender, APOE genetic status) and modifiable risk factors (MIND diet adherence and physical health) on cognition; furthermore, to determine if APOE genetic status modifies the relationship between MIND diet and cognition, longitudinally. Participants included middle-aged adults with a family history of AD enrolled in the Wisconsin Register for Alzheimer’s Prevention (WRAP) study. Latent Growth Curve (LGC) modeling was conducted to examine aims, assessing change across three visits (Visit 4 through Visit 6). Cognitive outcomes included previously established WRAP cognitive composite and factor scores. Upon examination of initial hypothesized models, empirical cognitive factor scores had significantly poorer model fit, and therefore, theoretically derived composite outcomes were used for structural modeling. Regarding physical health, waist-to-hip ratio (WHR) significantly reduced structural model fit across all cognitive outcomes, and therefore, WHR as a predictor of cognition was removed from analyses. Nonparametric correlations revealed, as expected, that WHR was negatively correlated with all cognitive outcomes (theoretical and empirical cognitive outcomes). Regarding diet, MIND diet adherence had unexpected significant negative effects on Theoretical Executive Functioning (TEF) growth over time; however, APOE risk scores did not significantly moderate this relationship. Improving the understanding of causative relationships among underlying hypothesized mechanisms of dietary benefits on cognition and AD risk is crucial to reduce the burden of AD. The null findings highlighted important gaps in the literature that warrant additional investigation, including further examination of these relationships in cognitively and demographically diverse individuals and exploration of cognitive phenotypes associated with APOE risk