Current Alzheimer Research - Volume 6, Issue 4, 2009

Current Alzheimer Research is delighted to present a special issue entitled ‘Perspective on Mild Cognitive Impairment (MCI)’. This special issue is based on scientific presentations given at the ‘Symposia on Mild Cognitive Impairment’, organized by the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, USA, from April 18-19, 2008. This issue contains a collection of eleven peer-reviewed articles on different aspects of MCI. These thought-provoking manuscripts contribute significantly to our understanding of the clinical features and neuropsychological aspects associated with the earliest stages of dementing illnesses. Trajectories of the cognitive impairment in sporadic and familial Alzheimer's disease (FAD) and frontotemporal dementia (FTD) are clearly discussed as well as the current therapeutic approaches. The role and importance of neuroimaging is also well represented by studies indicating that neurodegeneration begins well before current standards yield a diagnosis of dementia. Furthermore, the dimensions of care for the affected individuals and caregiver are presented. This special issue is organized and edited by Prof. Bernardino Ghetti, who reflects on the role of memories at the stage of life when they may be robbed by age-related disorders. On behalf of the Editorial Board and the publishers I deeply appreciate Dr. Ghetti and authors for their insightfulness and dedication. I am also indebted to the reviewers and others involved in this project for their hard work.

Full text available

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.

Primary Progressive Aphasia (PPA) is a neurodegenerative syndrome characterized by a gradual dissolution of language, but relative sparing of other cognitive domains during the initial stages of the disease. Research has led to substantial progress in understanding the clinical characteristics, genetics, and neuropathology of this syndrome. This article reviews the clinical criteria for diagnosing PPA, discusses the utility of defining the mild cognitive impairment (MCI) stage of PPA, and highlights some of the more recent research advances particularly in the area of pathology and genetics.

Frontotemporal dementia is a disorder of paralimbic prefrontal-insular circuitry. The disorder is often sporadic but can be caused by genetic mutations in tau, progranulin, valosin, TDP-43 and CHMP2b. The major clinical manifestations of FTD include addictive behaviors, disinhibition, apathy, overeating and loss of sympathy and empathy for others. Treatment is currently focused around symptoms but disease-modifying therapies seem feasible.

The definition of mild cognitive impairment (MCI) as a precursor for Alzheimer's disease (AD) represented an important step forward in diagnosing the illness in its earliest stage. However, diagnoses based principally on cognitive performance have limitations in that there is variability between centers in which tests are employed and in how they are interpreted. Advances in our understanding of imaging and biochemical changes occurring early in the illness have improved our ability to diagnose AD in this early phase and diagnostic criteria for AD have been proposed recently based on such biomarkers. Persons inheriting autosomal dominant mutations causing familial AD (FAD) are essentially certain to develop the disease. In our studies of preclinical persons at-risk for inheriting FAD, we applied MCI diagnostic criteria to carriers of FAD mutations to ascertain the extent to which they identified persons in the earliest stages of the clinical illness. Our results indicate the relative prevalence of MCI subtypes varies considerably depending on the tests used to measure cognition. Furthermore, we found that cognitive complaints in such persons were less predictive of mutation status than were informants' reports of cognitive loss. The study of FAD provides an opportunity to test various criteria for early AD and these observations should be taken into consideration in future iterations of such diagnostic criteria.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a multi-center study assessing neuroimaging in diagnosis and longitudinal monitoring. Amnestic Mild Cognitive Impairment (MCI) often represents a prodromal form of dementia, conferring a 10-15% annual risk of converting to probable AD. We analyzed baseline 1.5T MRI scans in 693 participants from the ADNI cohort divided into four groups by baseline diagnosis and one year MCI to probable AD conversion status to identify neuroimaging phenotypes associated with MCI and AD and potential predictive markers of imminent conversion. MP-RAGE scans were analyzed using publicly available voxel-based morphometry (VBM) and automated parcellation methods. Measures included global and hippocampal grey matter (GM) density, hippocampal and amygdalar volumes, and cortical thickness values from entorhinal cortex and other temporal and parietal lobe regions. The overall pattern of structural MRI changes in MCI (n=339) and AD (n=148) compared to healthy controls (HC, n=206) was similar to prior findings in smaller samples. MCI-Converters (n=62) demonstrated a very similar pattern of atrophic changes to the AD group up to a year before meeting clinical criteria for AD. Finally, a comparison of effect sizes for contrasts between the MCI-Converters and MCI-Stable (n=277) groups on MRI metrics indicated that degree of neurodegeneration of medial temporal structures was the best antecedent MRI marker of imminent conversion, with decreased hippocampal volume (left > right) being the most robust. Validation of imaging biomarkers is important as they can help enrich clinical trials of disease modifying agents by identifying individuals at highest risk for progression to AD.

Mild cognitive impairment (MCI), an intermediate stage between normalcy and dementia, is characterized by fewer symptoms and less functional decline than dementia with less established biological disease processes and is an attractive target for both symptomatic and disease progression therapies. It is always desirable to treat symptoms or slow disease at a stage where the individual is still largely functional. Therapeutic studies in MCI have either been symptomatic, usually of shorter duration or of longer multiyear terms to demonstrate whether disease progression is delayed. Symptomatic agents tested to date include donepezil, SGS-742, and Piracetam. No symptomatic drug study has demonstrated clinically convincing differences between placebo and the study medication. Disease progression trials in MCI investigations of 2 to 4 year durations have included donepezil, vitamin E, rivastigmine, galantamine and rofecoxib. None have demonstrated convincing effects in delaying longer term disease progression or conversion to dementia. Problems that may have undermined these trials; i) disease heterogeneity, ii) slow early progression of the disease, and iii) insensitive cognitive and functional instruments. Future MCI studies may benefit from the use of biomarkers such as apolipoprotein E (APOE4), cerebrospinal fluid amyloid-β 1-42 and Tau levels and PIB positivity on brain PET scans as well as more sensitive neuropsychological test measures may also more accurately reflect clinical changes related to drug effects.

The number of older adults with Alzheimer's disease and related disorders is expected to triple over the next 50 years. While we may be on the cusp of important therapeutic advances, such advances will not alter the disease course for millions of persons already affected. Hoping for technology to spare the health care system from the need to care for older adults with dementia is no longer tenable. Most older adults with dementia will receive their medical care in the primary care setting and this setting is not prepared to provide for the complex care needs of these vulnerable elders. With an increasing emphasis on earlier diagnosis of dementia, primary care in particular will come under increasing strain from this new care responsibility. While primary care may remain the hub of care for older adults, it cannot and should not be the whole of care. We need to design and test new models of care that integrate the larger health care system including medical care as well as community and family resources. The purpose of this paper to describe the current health care infrastructure with an emphasis on the role of primary care in providing care for older adults with dementia. We summarize recent innovative models of care seeking to provide an integrated and coordinated system of care for older adults with dementia. We present the case for a more aggressive agenda to improving our system of care for older adults with dementia through greater training, integration, and collaboration of care providers. This requires investments in the design and testing of an improved infrastructure for care that matches our national investment in the search for cure.

This paper is based on a presentation made during the Indiana Alzheimer Disease Center's Symposium on Mild Cognitive Impairment on April 19, 2008. The results of the ACTIVE study (Advanced Cognitive Training for Independent and Vital Elderly) were presented at the symposium including review of previously published study findings. The ACTIVE study is a multicenter, randomized, controlled clinical trial that has been examining the long-term effectiveness of cognitive training on enhancing mental abilities (memory, reasoning, and attention) and preserving activities of daily living (managing finances, taking medication, using the telephone, and driving) in older adults. Six centers across the eastern United States enrolled nearly 3000 people initially. Participants underwent detailed assessments of mental and functional ability on multiple occasions over several years of follow-up. ACTIVE has shown positive effects of cognitive training at 5 years post-intervention for basic mental abilities, health-related quality of life, and improved ability to perform instrumental activities of daily living (IADL). A subgroup analysis through 2 years of follow-up suggested that subjects with mild cognitive impairment (MCI) did not benefit from memory training; however, they did benefit, to the same degree as cognitively normal participants, from training in reasoning and speed of processing. This finding suggests that MCI may interfere with a person's ability to benefit from some forms of cognitive enhancement. Limitations of ACTIVE and directions for future research are reviewed.

The purpose of this paper is to describe commonalities of the lived experience of being a spouse caregiver of a person with mild cognitive impairment (MCI). The Colaizzi method of empirical phenomenology was used for inter-viewing and analyzing data obtained from 10 spouse caregivers of persons with MCI. Four major themes were found and labeled: (a) Putting the Puzzle Pieces Together-There Really is Something Wrong; (b) A Downward Spiral into a World of Silence; (c) Consequences to Caregivers of Living in a World of Silence; (d) Taking Charge of Care. The findings of this study provided rich data to guide interventions to help caregivers to improve their awareness of MCI, gain new information and skills to deal more effectively with and adjust to the caregiving of their spouse with MCI over the long-term.

The purpose of the paper is to describe common psychological and caregiving issues that can cause stress in family members of persons with mild cognitive impairment (PwMCI) in order to assist family members in providing care and support to the PwMCI while also caring for themselves over long periods of time. Because PwMCI and their family members have time to prepare for the future should the PwMCI no longer be able to participate in their own care, it is important that clinicians offer support, education, and referrals for services and interventions when needed. The results of a review and synthesis of the caregiving literature found that much information exists from educational and intervention programs designed to help caregivers of Alzheimer disease however little empirical information is available for clinicians to assist PwMCI and their family members. This paper provides valuable and practical information for clinicians and other care providers to assist family members of PwMCI to cope with the uncertainty of the diagnosis, prepare for the future, and manage their stress over the long-term.

A crucial need exists for reliable Alzheimer's disease (AD) diagnostic and prognostic tests. Given its intimate communication with the brain, the cerebrospinal fluid (CSF) has been surveyed intensively for reliable AD biomarkers. The heterogeneity of AD pathology and the unavoidable difficulties associated with the clinical diagnosis and differentiation of this dementia from other pathologies have confounded biomarker studies in antemortem CSF samples. Using postmortem ventricular CSF (V-CSF) pools, two-dimensional difference gel electrophoresis (2D DIGE) analyses revealed a set of proteins that showed significant differences between neuropathologically-diagnosed AD and elderly nondemented controls (NDC), as well as subjects with non-AD dementias. The 2D DIGE system identified a set of 21 different protein biomarkers. This panel of proteins probably reflects fundamental pathological changes that are divergent from both normal aging and non-AD dementias.