As individuals age, the quality of cognitive function becomes an increasingly important topic. The concept of mild cognitive impairment (MCI) has evolved over the past 2 decades to represent a state ...of cognitive function between that seen in normal aging and dementia. As such, it is important for health care providers to be aware of the condition and place it in the appropriate clinical context.
Numerous international population-based studies have been conducted to document the frequency of MCI, estimating its prevalence to be between 15% and 20% in persons 60 years and older, making it a common condition encountered by clinicians. The annual rate in which MCI progresses to dementia varies between 8% and 15% per year, implying that it is an important condition to identify and treat. In those MCI cases destined to develop Alzheimer disease, biomarkers are emerging to help identify etiology and predict progression. However, not all MCI is due to Alzheimer disease, and identifying subtypes is important for possible treatment and counseling. If treatable causes are identified, the person with MCI might improve.
MCI is an important clinical entity to identify, and while uncertainties persist, clinicians need to be aware of its diagnostic features to enable them to counsel patients. MCI remains an active area of research as numerous randomized controlled trials are being conducted to develop effective treatments.
Along with a general decline in overall health, most chronic degenerative human diseases are inherently associated with increasing age. Age-associated cognitive impairments and neurodegenerative ...diseases, such as Parkinson's and Alzheimer's diseases, are potentially debilitating conditions that lack viable options for treatment, resulting in a tremendous economic and societal cost. Most high-profile clinical trials for neurodegenerative diseases have led to inefficacious results, suggesting that novel approaches to treating these pathologies are needed. Numerous recent studies have demonstrated that senescent cells, which are characterized by sustained cell cycle arrest and production of a distinct senescence-associated secretory phenotype, accumulate with age and at sites of age-related diseases throughout the body, where they actively promote tissue deterioration. Cells with features of senescence have been detected in the context of brain aging and neurodegenerative disease, suggesting that they may also promote dysfunction. Here, we discuss the evidence implicating senescent cells in neurodegenerative diseases, the mechanistic contribution of these cells that may actively drive neurodegeneration, and how these cells or their effects may be targeted therapeutically.
Alzheimer's Disease (AD) currently affects more than 5 million Americans, with numbers expected to grow dramatically as the population ages. The pathophysiological changes in AD patients begin ...decades before the onset of dementia, highlighting the urgent need for the development of early diagnostic methods. Compelling data demonstrate that increased levels of amyloid-beta compromise multiple cellular pathways; thus, the investigation of changes in various cellular networks is essential to advance our understanding of early disease mechanisms and to identify novel therapeutic targets. We applied a liquid chromatography/mass spectrometry-based non-targeted metabolomics approach to determine global metabolic changes in plasma and cerebrospinal fluid (CSF) from the same individuals with different AD severity. Metabolic profiling detected a total of significantly altered 342 plasma and 351 CSF metabolites, of which 22% were identified. Based on the changes of >150 metabolites, we found 23 altered canonical pathways in plasma and 20 in CSF in mild cognitive impairment (MCI) vs. cognitively normal (CN) individuals with a false discovery rate <0.05. The number of affected pathways increased with disease severity in both fluids. Lysine metabolism in plasma and the Krebs cycle in CSF were significantly affected in MCI vs. CN. Cholesterol and sphingolipids transport was altered in both CSF and plasma of AD vs. CN. Other 30 canonical pathways significantly disturbed in MCI and AD patients included energy metabolism, Krebs cycle, mitochondrial function, neurotransmitter and amino acid metabolism, and lipid biosynthesis. Pathways in plasma that discriminated between all groups included polyamine, lysine, tryptophan metabolism, and aminoacyl-tRNA biosynthesis; and in CSF involved cortisone and prostaglandin 2 biosynthesis and metabolism. Our data suggest metabolomics could advance our understanding of the early disease mechanisms shared in progression from CN to MCI and to AD.
A seismic shift in our understanding of the ability to diagnose Alzheimer disease (AD) is occurring. For the last several decades, AD has been a clinical-pathologic diagnosis, and this ...conceptualization of the disease has served the field well. Typically, the clinician would identify a syndrome such as mild cognitive impairment or dementia, and label the condition as "probable AD" since the diagnosis of definite AD could not be made until an autopsy revealed the presence of amyloid plaques and tau-based neurofibrillary tangles. However, with the advent of biomarkers for AD including neuroimaging and CSF, the identification of AD pathology can be made in life, which greatly enhances the ability of clinicians to be precise about the underlying etiology of a clinical syndrome. Hypothetical models of the temporal relation among the pathologic elements and the clinical symptoms have been proposed and have influenced the field enormously. This has enabled clinicians to be specific about the underlying cause of a given clinical syndrome. As such, the diagnostic capability of the clinician is evolving. However, AD pathology is only a component of the puzzle describing the causes of cognitive changes in aging. Most often, there is a multitude of pathologic entities contributing to the neuropathologic explanation of cognitive changes in aging. AD changes contribute important elements to the diagnosis, but the final answer is more complex. The field of aging and dementia will have to incorporate these additional elements.
A rapidly growing literature strongly suggests that exercise, specifically aerobic exercise, may attenuate cognitive impairment and reduce dementia risk. We used PubMed (keywords exercise and ...cognition) and manuscript bibliographies to examine the published evidence of a cognitive neuroprotective effect of exercise. Meta-analyses of prospective studies documented a significantly reduced risk of dementia associated with midlife exercise; similarly, midlife exercise significantly reduced later risks of mild cognitive impairment in several studies. Among patients with dementia or mild cognitive impairment, randomized controlled trials (RCTs) documented better cognitive scores after 6 to 12 months of exercise compared with sedentary controls. Meta-analyses of RCTs of aerobic exercise in healthy adults were also associated with significantly improved cognitive scores. One year of aerobic exercise in a large RCT of seniors was associated with significantly larger hippocampal volumes and better spatial memory; other RCTs in seniors documented attenuation of age-related gray matter volume loss with aerobic exercise. Cross-sectional studies similarly reported significantly larger hippocampal or gray matter volumes among physically fit seniors compared with unfit seniors. Brain cognitive networks studied with functional magnetic resonance imaging display improved connectivity after 6 to 12 months of exercise. Animal studies indicate that exercise facilitates neuroplasticity via a variety of biomechanisms, with improved learning outcomes. Induction of brain neurotrophic factors by exercise has been confirmed in multiple animal studies, with indirect evidence for this process in humans. Besides a brain neuroprotective effect, physical exercise may also attenuate cognitive decline via mitigation of cerebrovascular risk, including the contribution of small vessel disease to dementia. Exercise should not be overlooked as an important therapeutic strategy.
Summary In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer's disease (AD). The model was received with interest because we described the temporal evolution of AD ...biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.
Task-free functional magnetic resonance imaging (TF-fMRI) has great potential for advancing the understanding and treatment of neurologic illness. However, as with all measures of neural activity, ...variability is a hallmark of intrinsic connectivity networks (ICNs) identified by TF-fMRI. This variability has hampered efforts to define a robust metric of connectivity suitable as a biomarker for neurologic illness. We hypothesized that some of this variability rather than representing noise in the measurement process, is related to a fundamental feature of connectivity within ICNs, which is their non-stationary nature. To test this hypothesis, we used a large (n = 892) population-based sample of older subjects to construct a well characterized atlas of 68 functional regions, which were categorized based on independent component analysis network of origin, anatomical locations, and a functional meta-analysis. These regions were then used to construct dynamic graphical representations of brain connectivity within a sliding time window for each subject. This allowed us to demonstrate the non-stationary nature of the brain's modular organization and assign each region to a "meta-modular" group. Using this grouping, we then compared dwell time in strong sub-network configurations of the default mode network (DMN) between 28 subjects with Alzheimer's dementia and 56 cognitively normal elderly subjects matched 1:2 on age, gender, and education. We found that differences in connectivity we and others have previously observed in Alzheimer's disease can be explained by differences in dwell time in DMN sub-network configurations, rather than steady state connectivity magnitude. DMN dwell time in specific modular configurations may also underlie the TF-fMRI findings that have been described in mild cognitive impairment and cognitively normal subjects who are at risk for Alzheimer's dementia.
Mild cognitive impairment and mild dementia are common problems in the elderly. Primary care physicians are the first point of contact for most patients with these disorders and should be familiar ...with their diagnosis, prognosis, and management. Both mild cognitive impairment and mild dementia are characterized by objective evidence of cognitive impairment. The main distinctions between mild cognitive impairment and mild dementia are that in the latter, more than one cognitive domain is invariably involved and substantial interference with daily life is evident. The diagnosis of mild cognitive impairment and mild dementia is based mainly on the history and cognitive examination. The prognosis for mild cognitive impairment and mild dementia is an important motivation for diagnosis because in both, there is a heightened risk for further cognitive decline. The etiology of mild cognitive impairment and mild dementia can often be established through the clinical examination, although imaging and other laboratory tests may also contribute. Although Alzheimer disease is the most common cause of both, cerebrovascular disease and Lewy body disease make important contributions. Pharmacological treatments are of modest value in mild dementia due to Alzheimer disease, and there are no approved pharmacological treatments for mild cognitive impairment of any etiology. Nonetheless, new-onset cognitive impairment is a worrisome symptom to patients and families that demands answers and advice. If a patient is having difficulties managing medications, finances, or transportation independently, diagnosis and intervention are necessary to ensure the health and safety of the patient.
The field of aging and dementia research is advancing rapidly toward the stage of earlier identification of clinical symptoms. Ultimately, clinicians would like to be able to identify individuals who ...are asymptomatic but at risk for developing dementia. In the interim, the construct of mild cognitive impairment (MCI) has come to represent an intermediate clinical state between the cognitive changes of aging and the very earliest features of Alzheimer's disease. A great deal of research has been generated in the past several years on MCI, and epidemiologic studies are characterizing its frequency in the general population. There are predictors of a more rapid progression from MCI to Alzheimer's disease, and these studies are suggesting techniques for altering future clinical trials. The neuropathology of MCI is intermediate between the neuropathologic changes of aging and fully developed Alzheimer's disease. The breadth of research in MCI is expanding and will be reviewed.
PDF
