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1.  Epidemiological Pathology of Dementia: Attributable-Risks at Death in the Medical Research Council Cognitive Function and Ageing Study 
PLoS Medicine  2009;6(11):e1000180.
Researchers from the Medical Research Council Cognitive Function and Ageing Neuropathology Study carry out an analysis of brain pathologies contributing to dementia, within a cohort of elderly individuals in the UK who agreed to brain donation.
Background
Dementia drug development aims to modulate pathological processes that cause clinical syndromes. Population data (epidemiological neuropathology) will help to model and predict the potential impact of such therapies on dementia burden in older people. Presently this can only be explored through post mortem findings. We report the attributable risks (ARs) for dementia at death for common age-related degenerative and vascular pathologies, and other factors, in the MRC Cognitive Function and Ageing Study (MRC CFAS).
Methods and Findings
A multicentre, prospective, longitudinal study of older people in the UK was linked to a brain donation programme. Neuropathology of 456 consecutive brain donations assessed degenerative and vascular pathologies. Logistic regression modelling, with bootstrapping and sensitivity analyses, was used to estimate AR at death for dementia for specific pathologies and other factors. The main contributors to AR at death for dementia in MRC CFAS were age (18%), small brain (12%), neocortical neuritic plaques (8%) and neurofibrillary tangles (11%), small vessel disease (12%), multiple vascular pathologies (9%), and hippocampal atrophy (10%). Other significant factors include cerebral amyloid angiopathy (7%) and Lewy bodies (3%).
Conclusions
Such AR estimates cannot be derived from the living population; rather they estimate the relative contribution of specific pathologies to dementia at death. We found that multiple pathologies determine the overall burden of dementia. The impact of therapy targeted to a specific pathology may be profound when the dementia is relatively “pure,” but may be less impressive for the majority with mixed disease, and in terms of the population. These data justify a range of strategies, and combination therapies, to combat the degenerative and vascular determinants of cognitive decline and dementia.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Losing one's belongings and forgetting people's names is often a normal part of aging. But increasing forgetfulness can also be a sign of dementia, a group of symptoms caused by several disorders that affect the structure of the brain. The commonest form of dementia is Alzheimer disease. In this, protein clumps called plaques and neurofibrillary tangles form in the brain and cause its degeneration. Vascular dementia, in which problems with blood circulation deprive parts of the brain of oxygen, is also common. People with dementia have problems with two or more “cognitive” functions—thinking, language, memory, understanding, and judgment. As the disease progresses, they gradually lose their ability to deal with normal daily activities until they need total care, their personality often changes, and they may become agitated or aggressive. Dementia is rare before the age of 65 years but about a quarter of people over 85 years old have dementia. Because more people live to a ripe old age these days, the number of people with dementia is increasing. According to the latest estimates, about 35 million people now have dementia and by 2050, 115 million may have the disorder.
Why Was This Study Done?
There is no cure for dementia but many drugs designed to modulate specific abnormal (pathological) changes in the brain that can cause the symptoms of dementia are being developed. To assess the likely impact of these potentially expensive new therapies, experts need to know what proportion of dementia is associated with each type of brain pathology. Although some brain changes can be detected in living brains with techniques such as computed tomography brain scans, most brain changes can only be studied in brains taken from people after death (post mortem brains). In this study, which is part of the UK Medical Research Council Cognitive Function and Ageing Study (MRC CFAS), the researchers look for associations between dementia in elderly people and pathological changes in their post mortem brains and estimate the attributable-risk (AR) for dementia at death associated with specific pathological features in the brain. That is, they estimate the proportion of dementia directly attributable to each type of pathology.
What Did the Researchers Do and Find?
Nearly 20 years ago, the MRC CFAS interviewed more than 18,000 people aged 65 years or older recruited at six sites in England and Wales to determine their cognitive function and their ability to deal with daily activities. 20% of the participants, which included people with and without cognitive impairment, were then assessed in more detail and invited to donate their brains for post mortem examination. As of 2004, 456 individuals had donated their brains. The dementia status of these donors was established using data from their assessment interviews and death certificates, and from interviews with relatives and carers, and their brains were carefully examined for abnormal changes. The researchers then used statistical methods to estimate the AR for dementia at death associated with various abnormal brain changes. The main contributors to AR for dementia at death included age (18% of dementia at death was attributable to this factor), plaques (8%), and neurofibrillary tangles (11%) in a brain region called the neocortex, small blood vessel disease (12%), and multiple abnormal changes in blood vessels (9%).
What Do These Findings Mean?
These findings suggest that multiple abnormal brain changes determine the overall burden of dementia. Importantly, they also suggest that dementia is often associated with mixed pathological changes—many people with dementia had brain changes consistent with both Alzheimer disease and vascular dementia. Because people with dementia live for variable lengths of time during which the abnormal changes in their brain are likely to alter, it may be difficult to extrapolate these findings to living populations of elderly people. Furthermore, only a small percentage of the MRC CFAS participants have donated their brains so the findings of this study may not apply to the general population. Nevertheless, these findings suggest that the new therapies currently under development may do little to reduce the overall burden of dementia because most people's dementia involves multiple pathologies. Consequently, it may be necessary to develop a range of strategies and combination therapies to deal with the ongoing dementia epidemic.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000180.
The US National Institute on Aging provides information for patients and carers about forgetfulness and about Alzheimer disease (in English and Spanish)
The US National Institute of Neurological Disorders and Stroke provides information about dementia (in English and Spanish)
The UK National Health Service Choices Web site also provides detailed information for patients and their carers about dementia and about Alzheimer disease
MedlinePlus provides links to additional resources about dementia and Alzheimer disease (in English and Spanish)
More information about the UK Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) is available
doi:10.1371/journal.pmed.1000180
PMCID: PMC2765638  PMID: 19901977
2.  Cognitive reserve in ageing and Alzheimer's disease 
Lancet neurology  2012;11(11):1006-1012.
The concept of reserve accounts for individual differences in susceptibility to age-related brain changes or Alzheimer's disease-related pathology. There is evidence that some people can tolerate more of these changes than others and still maintain function. Epidemiologic studies suggest that lifetime exposures including educational and occupational attainment, and leisure activities in late life, can increase this reserve. For example, there is a reduced risk of developing Alzheimer's disease in individuals with higher educational or occupational attainment. It is convenient to think of two types of reserve: brain reserve, which refers to actual differences in the brain itself that may increase tolerance of pathology, and cognitive reserve. Cognitive reserve refers to individual differences in how tasks are performed that may allow some people to be more resilient than others. The concept of cognitive reserve holds out the promise of interventions that could slow cognitive aging or reduce the risk of dementia.
doi:10.1016/S1474-4422(12)70191-6
PMCID: PMC3507991  PMID: 23079557
3.  Prevalence, Distribution, and Impact of Mild Cognitive Impairment in Latin America, China, and India: A 10/66 Population-Based Study 
PLoS Medicine  2012;9(2):e1001170.
A set of cross-sectional surveys carried out in Cuba, Dominican Republic, Peru, Mexico, Venezuela, Puerto Rico, China, and India reveal the prevalence and between-country variation in mild cognitive impairment at a population level.
Background
Rapid demographic ageing is a growing public health issue in many low- and middle-income countries (LAMICs). Mild cognitive impairment (MCI) is a construct frequently used to define groups of people who may be at risk of developing dementia, crucial for targeting preventative interventions. However, little is known about the prevalence or impact of MCI in LAMIC settings.
Methods and Findings
Data were analysed from cross-sectional surveys established by the 10/66 Dementia Research Group and carried out in Cuba, Dominican Republic, Peru, Mexico, Venezuela, Puerto Rico, China, and India on 15,376 individuals aged 65+ without dementia. Standardised assessments of mental and physical health, and cognitive function were carried out including informant interviews. An algorithm was developed to define Mayo Clinic amnestic MCI (aMCI). Disability (12-item World Health Organization disability assessment schedule [WHODAS]) and informant-reported neuropsychiatric symptoms (neuropsychiatric inventory [NPI-Q]) were measured. After adjustment, aMCI was associated with disability, anxiety, apathy, and irritability (but not depression); between-country heterogeneity in these associations was only significant for disability. The crude prevalence of aMCI ranged from 0.8% in China to 4.3% in India. Country differences changed little (range 0.6%–4.6%) after standardization for age, gender, and education level. In pooled estimates, aMCI was modestly associated with male gender and fewer assets but was not associated with age or education. There was no significant between-country variation in these demographic associations.
Conclusions
An algorithm-derived diagnosis of aMCI showed few sociodemographic associations but was consistently associated with higher disability and neuropsychiatric symptoms in addition to showing substantial variation in prevalence across LAMIC populations. Longitudinal data are needed to confirm findings—in particular, to investigate the predictive validity of aMCI in these settings and risk/protective factors for progression to dementia; however, the large number affected has important implications in these rapidly ageing settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, more than 35 million people worldwide have dementia, a group of brain disorders characterized by an irreversible decline in memory, problem solving, communication, and other “cognitive” functions. Dementia, the commonest form of which is Alzheimer's disease, mainly affects older people and, because more people than ever are living to a ripe old age, experts estimate that, by 2050, more than 115 million people will have dementia. At present, there is no cure for dementia although drugs can be used to manage some of the symptoms. Risk factors for dementia include physical inactivity, infrequent participation in mentally or socially stimulating activities, and common vascular risk factors such as high blood pressure, diabetes, and smoking. In addition, some studies have reported that mild cognitive impairment (MCI) is associated with an increased risk of dementia. MCI can be seen as an intermediate state between normal cognitive aging (becoming increasingly forgetful) and dementia although many people with MCI never develop dementia, and some types of MCI can be static or self-limiting. Individuals with MCI have cognitive problems that are more severe than those normally seen in people of a similar age but they have no other symptoms of dementia and are able to look after themselves. The best studied form of MCI—amnestic MCI (aMCI)—is characterized by memory problems such as misplacing things and forgetting appointments.
Why Was This Study Done?
Much of the expected increase in dementia will occur in low and middle income countries (LAMICs) because these countries have rapidly aging populations. Given that aMCI is frequently used to define groups of people who may be at risk of developing dementia, it would be useful to know what proportion of community-dwelling older adults in LAMICs have aMCI (the prevalence of aMCI). Such information might help governments plan their future health care and social support needs. In this cross-sectional, population-based study, the researchers estimate the prevalence of aMCI in eight LAMICs using data collected by the 10/66 Dementia Research Group. They also investigate the association of aMCI with sociodemographic factors (for example, age, gender, and education), disability, and neuropsychiatric symptoms such as anxiety, apathy, irritability, and depression. A cross-sectional study collects data on a population at a single time point; the 10/66 Dementia Research Group is building an evidence base to inform the development and implementation of policies for improving the health and social welfare of older people in LAMICs, particularly people with dementia.
What Did the Researchers Do and Find?
In cross-sectional surveys carried out in six Latin American LAMICS, China, and India, more than 15,000 elderly individuals without dementia completed standardized assessments of their mental and physical health and their cognitive function. Interviews with relatives and carers provided further details about the participant's cognitive decline and about neuropsychiatric symptoms. The researchers developed an algorithm (set of formulae) that used the data collected in these surveys to diagnose aMCI in the study participants. Finally, they used statistical methods to analyze the prevalence, distribution, and impact of aMCI in the eight LAMICs. The researchers report that aMCI was associated with disability, anxiety, apathy, and irritability but not with depression and that the prevalence of aMCI ranged from 0.8% in China to 4.3% in India. Other analyses show that, considered across all eight countries, aMCI was modestly associated with being male (men had a slightly higher prevalence of aMCI than women) and with having fewer assets but was not associated with age or education.
What Do These Findings Mean?
These findings suggest that aMCI, as diagnosed using the algorithm developed by the researchers, is consistently associated with higher disability and with neuropsychiatric symptoms in the LAMICs studied but not with most sociodemographic factors. Because prevalidated and standardized measurements were applied consistently in all the countries and a common algorithm was used to define aMCI, these findings also suggest that the prevalence of aMCI varies markedly among LAMIC populations and is similar to or slightly lower than the prevalence most often reported for European and North American populations. Although longitudinal studies are now needed to investigate the extent to which aMCI can be used as risk marker for further cognitive decline and dementia in these settings, the large absolute numbers of older people with aMCI in LAMICs revealed here potentially has important implications for health care and social service planning in these rapidly aging and populous regions of the world.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001170.
Alzheimer's Disease International is the international federation of Alzheimer associations around the world; it provides links to individual associations, information about dementia, and links to three World Alzheimer Reports; information about the 10/66 Dementia Research Group is also available on this web site
The Alzheimer's Society provides information for patients and carers about dementia, including information on MCI and personal stories about living with dementia
The Alzheimer's Association also provides information for patients and carers about dementia and about MCI, and personal stories about dementia
A BBC radio program that includes an interview with a man with MCI is available
MedlinePlus provides links to further resources about MCI and dementia (in English and Spanish)
doi:10.1371/journal.pmed.1001170
PMCID: PMC3274506  PMID: 22346736
4.  Dementia before Death in Ageing Societies— The Promise of Prevention and the Reality 
PLoS Medicine  2006;3(10):e397.
Background
Dementia and severe cognitive impairment are very closely linked to ageing. The longer we live the more likely we are to suffer from these conditions. Given population increases in longevity it is important to understand not only risk and protective factors for dementia and severe cognitive impairment at given ages but also whether protection affects cumulative risk. This can be explored by examining the effect on cumulative risk by time of death of factors found consistently to reduce risk at particular ages, such as education and social status.
Methods and Findings
In this analysis we report the prevalence of dementia and severe cognitive impairment in the year before death in a large population sample. In the Medical Research Council Cognitive Function and Ageing Study (a 10-y population-based cohort study of individuals 65 and over in England and Wales), these prevalences have been estimated by age, sex, social class, and education. Differences have been explored using logistic regression. The overall prevalence of dementia at death was 30%. There was a strong increasing trend for dementia with age from 6% for those aged 65–69 y at time of death to 58% for those aged 95 y and above at time of death. Higher prevalences were seen for severe cognitive impairment, with similar patterns. People with higher education and social class had significantly reduced dementia and severe cognitive impairment before death, but the absolute difference was small (under 10%).
Conclusions
Reducing risk for dementia at a given age will lead to further extension of life, thus cumulative risk (even in populations at lower risk for given ages) remains high. Ageing of populations is likely to result in an increase in the number of people dying with dementia and severe cognitive impairment even in the presence of preventative programmes. Policy development and research for dementia must address the needs of individuals who will continue to experience these conditions before death.
The overall prevalence of dementia at death in this large study was 30%. Ageing of populations is likely to result in an increase in the number of people dying with dementia even in the presence of preventative programmes.
Editors' Summary
Background.
Severe cognitive impairment and its advanced form, dementia, are among the most difficult problems associated with aging in industrialized countries. Age-associated decline in mental functioning is also expected to become more common in developing countries as improvement of conditions that affect health leads to longer life expectancies. Although the risk of cognitive impairment is known to increase with age, the number of people who suffer from loss of mental abilities in the last years of their lives has not been well studied, as such persons are usually reported to have died from other causes. Further, because the very elderly are seldom included in prevention studies, it is not known whether factors found to reduce the risk of developing dementia by a given age will provide protection until the end of life.
Why Was This Study Done?
This study was designed to follow a representative population of aged people over several years to estimate the risk of developing cognitive impairment or dementia near the end of life and to determine whether factors such as education and social class, which may be protective earlier in life, can ultimately prevent decline in mental functioning.
What Did the Researchers Do and Find?
Using standardized assessments of cognitive status, the researchers interviewed people age 65 and over at six sites representing rural and urban areas in the United Kingdom. Interviews were conducted at regular intervals over ten years. Of approximately 12,000 study participants who had died by the time of this report, just over 2,500 had an assessment for dementia within one year before dying. Of this group, those who died between ages 65 and 69 had a 6% chance of dying with dementia, and those who died above age 95 had a 58% chance of dying with dementia. When moderate and severe cognitive impairment were considered together, the rate in people above age 95 reached almost 80%. Women were more likely to develop dementia than men, even after taking into account the fact that women tend to live longer than men. A higher level of education was associated with only a slightly lower risk of dementia before death.
What Do These Findings Mean?
According to these results, as the number of aged persons increases (with improved health care, preventive medicine, and healthier lifestyles), the chances of developing dementia in the last years of life will continue to increase. Factors believed to protect against dementia at earlier times may be of little effect at the end of life. Planning for aging societies must therefore include not only research into treatments and preventive efforts to reduce the impact of dementia at the end of life, but also realistic allocation of resources to support individuals and their caregivers who must deal with the difficulties of cognitive decline.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030397.
Web site of the Medical Research Council Cognitive Function and Ageing Study
Web site of the Alzheimer's Association
Wikipedia entry on dementia (note: Wikipedia is a free Internet encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030397
PMCID: PMC1626550  PMID: 17076551
5.  Cognitive Reserve Moderates the Association Between Hippocampal Volume and Episodic Memory in Middle Age 
Neuropsychologia  2013;51(6):1124-1131.
Cognitive reserve is hypothesized to help people withstand greater brain pathology without manifesting clinical symptoms, and may be regarded as a preventive factor of dementia. It is unclear whether the effect of cognitive reserve is evident only among the older adults or after conversion to dementia, or if it can also be seen earlier in life before the prominent effects of cognitive aging become apparent. While finding a main effect of cognitive reserve on cognitive outcome may be consistent with the reserve hypothesis, in our view, it is unnecessary to invoke the idea of reserve if only a main effect is present. Rather, it is the interaction between a measure of reserve and a brain measure on cognitive outcome that is key for confirming that the effects of brain pathology affect people differently according to their cognitive reserve. We studied whether general cognitive ability at an average age of 20 years, as a direct measure of cognitive reserve, moderates the association between hippocampal volume and episodic memory performance in 494 middle-aged men ages 51 to 60. Whereas there was no statistically significant direct relationship between hippocampal volume and episodic memory performance in middle age, we found a statistically significant interaction such that there was a positive association between hippocampal volume and episodic memory only among people with lower general cognitive ability at age 20, i.e., lower levels of cognitive reserve. Our results provide support for the hypothesis that cognitive reserve moderates the relationship between brain structure and cognition in middle age, well before the onset of dementia.
doi:10.1016/j.neuropsychologia.2013.02.022
PMCID: PMC3660613  PMID: 23499725
cognitive reserve; general cognitive ability; episodic memory; hippocampus; verbal learning
6.  Cortical Neuritic Plaques and Hippocampal Neurofibrillary Tangles are Related to Dementia Severity in Elderly Schizophrenia Patients 
Schizophrenia research  2010;116(1):90-96.
Cognitive decline has been described in elderly patients with schizophrenia, but the underlying pathology remains unknown. Some studies report increases in plaques and neurofibrillary tangles, but there is no evidence for an increased risk for Alzheimer’s disease (AD) in elderly schizophrenics. Models of a decreased cerebral reserve suggest that increases in AD-related neuropathology below the threshold for a neuropathological diagnosis could be related to dementia severity in elderly schizophrenia patients. We tested this hypothesis in 110 autopsy specimens of schizophrenia patients , without a neuropatholgical diagnosis of AD or other neurdegenerative disorders. Furthermore, we assessed the effects of apolipoprotein E (ApoE) status, a known genetic risk factor for AD. Measures of density of neuritic plaques were obtained in five cortical regions, and the degree of hippocampal neurofibrillary tangles was rated. Dementia severity was measured prior to postmortem using the Clinical Dementia Rating (CDR) scale. In multivariate analyses of variance were conducted with the factors dementia severity, by ApoE4 carrier status. Hippocampal neurofibrillary tangles correlated with increased dementia severity (p < .05). Neuritic plaque density increased with greater dementia severity (p < .005), and ApoE4 carrier status (p < .005), and these differences were magnified by ApoE4 carrier status (p < .01). Even below the threshold for a neuropathological diagnosis of AD, neuritic plaques and hippocampal neurofibrillary tangles are associated with dementia severity in schizophrenia patients, even more so in the presence of genetic risk factors, suggesting that a decreased cerebral reserve in elderly schizophrenics may increase susceptibilty for dementia.
doi:10.1016/j.schres.2009.10.013
PMCID: PMC2795077  PMID: 19896333
Schizophrenia; Alzheimer’s Disease; Neuropathology
7.  The dementia and disability project in Thai elderly: rational, design, methodology and early results 
BMC Neurology  2013;13:3.
Background
A strong inverse relationship of functional limitation and socioeconomic status has been established in western ageing society. Functional limitation can be related to chronic diseases, disuse, cognitive decline, and ageing. Among chronic diseases in the Thai population, cerebrovascular diseases, diabetes, and arthritis are common. These factors are known to contribute to disability and poor quality of life in the elder population. Neuropsychiatric problems, cognitive decline, dementia, and cultural issues in elderly people also can alter the quality of life of the elderly.
Methods
The Dementia and Disability Project in Thai Elderly (DDP) aims at comprehensively assessing community dwelling Thai elderly to understand the relationship between disability and motor function, neuropsychiatric symptoms, cognitive function, and chronic diseases. The DDP is the first study to look at the prevalence and etiology of dementia and of mild cognitive impairment (MCI) in Thai elders and to explore the relationship of cognition, disability, small vessel diseases and cortical degeneration with neuroimaging in Thai elderly people. 1998 Thai elders were screened in 2004–2006 and diagnosed as having MCI or dementia. 223 elders with MCI or dementia and cognitively normal elderly had brain magnetic resonance imaging (MRI) or at baseline. 319 elders from the 3 groups had blood tests to investigate the risks and possible etiologies of dementia including genotyping at baseline.
Results
The mean age of elders in this study is 69.51(SD=6.71, min=60, max=95) years. 689(34.9%) are men and 1284(65.1%) are women. Mean body weight was 58.36(SD=11.20) kgs. The regression model reveals that performance on gait and balance and serum triglyceride predicts activity of daily living performance (adjusted r2 = 0.280, f=2.644, p=0.003). The majority of abnormal gait in Thai elders was lower level gait disturbance. Only 1.5% (29/1952) had highest level gait disorders. 39.5% of 1964 subjects were free of chronic diseases. Treatment gap (indicating those who have untreated or inadequate treatment) of diabetes mellitus and hypertension in Thai elders in this study was 37% and 55.5% respectively. 62.6% of Thai elders have ApoE3E3 allele. Prevalence of positive ApoE4 gene in this study is 22.85%. 38.6% of Thai elders who had MRI brain study have moderate to severe white matter lesions.
Conclusion
The large and comprehensive set of measurements in DDP allows a wide-ranging explanation of the functional and clinical features to be investigated in relation to white matter lesions or cortical atrophy of the brain in Thai elderly population. An almost 2 year follow up was made available to those with MCI and dementia and some of the cognitively normal elderly. The longitudinal design will provide great understanding of the possible contributors to disability in the elderly and to the progression of cognitive decline in Thai elders.
doi:10.1186/1471-2377-13-3
PMCID: PMC3552988  PMID: 23305293
Mild cognitive impairment; Dementia; Alzheimer disease; Disability; White matter lesions; Thailand
8.  Cognitive activities delay onset of memory decline in persons who develop dementia 
Neurology  2009;73(5):356-361.
Background:
Persons destined to develop dementia experience an accelerated rate of decline in cognitive ability, particularly in memory. Early life education and participation in cognitively stimulating leisure activities later in life are 2 factors thought to reflect cognitive reserve, which may delay the onset of the memory decline in the preclinical stages of dementia.
Methods:
We followed 488 initially cognitively intact community residing individuals with epidemiologic, clinical, and cognitive assessments every 12 to 18 months in the Bronx Aging Study. We assessed the influence of self-reported participation in cognitively stimulating leisure activities on the onset of accelerated memory decline as measured by the Buschke Selective Reminding Test in 101 individuals who developed incident dementia using a change point model.
Results:
Each additional self-reported day of cognitive activity at baseline delayed the onset of accelerated memory decline by 0.18 years. Higher baseline levels of cognitive activity were associated with more rapid memory decline after that onset. Inclusion of education did not significantly add to the fit of the model beyond the effect of cognitive activities.
Conclusions:
Our findings show that late life cognitive activities influence cognitive reserve independently of education. The effect of early life education on cognitive reserve may be mediated by cognitive activity later in life. Alternatively, early life education may be a determinant of cognitive reserve, and individuals with more education may choose to participate in cognitive activities without influencing reserve. Future studies should examine the efficacy of increasing participation in cognitive activities to prevent or delay dementia.
GLOSSARY
= Alzheimer disease;
= baseline;
= Cognitive Activity Scale;
= confidence interval;
= Diagnostic and Statistical Manual of Mental Disorders;
= diagnosis;
= National Institute on Aging;
= Selective Reminding Test;
= Wechsler Adult Intelligence Scale Verbal IQ.
doi:10.1212/WNL.0b013e3181b04ae3
PMCID: PMC2725932  PMID: 19652139
9.  Psychosocial Factors That Shape Patient and Carer Experiences of Dementia Diagnosis and Treatment: A Systematic Review of Qualitative Studies 
PLoS Medicine  2012;9(10):e1001331.
A systematic review of qualitative studies conducted by Frances Bunn and colleagues identifies and describes the experiences of patients and caregivers on receiving and adapting to a diagnosis of dementia.
Background
Early diagnosis and intervention for people with dementia is increasingly considered a priority, but practitioners are concerned with the effects of earlier diagnosis and interventions on patients and caregivers. This systematic review evaluates the qualitative evidence about how people accommodate and adapt to the diagnosis of dementia and its immediate consequences, to guide practice.
Methods and Findings
We systematically reviewed qualitative studies exploring experiences of community-dwelling individuals with dementia, and their carers, around diagnosis and the transition to becoming a person with dementia. We searched PubMed, PsychINFO, Embase, CINAHL, and the British Nursing Index (all searched in May 2010 with no date restrictions; PubMed search updated in February 2012), checked reference lists, and undertook citation searches in PubMed and Google Scholar (ongoing to September 2011). We used thematic synthesis to identify key themes, commonalities, barriers to earlier diagnosis, and support identified as helpful. We identified 126 papers reporting 102 studies including a total of 3,095 participants. Three overarching themes emerged from our analysis: (1) pathways through diagnosis, including its impact on identity, roles, and relationships; (2) resolving conflicts to accommodate a diagnosis, including the acceptability of support, focusing on the present or the future, and the use or avoidance of knowledge; and (3) strategies and support to minimise the impact of dementia. Consistent barriers to diagnosis include stigma, normalisation of symptoms, and lack of knowledge. Studies report a lack of specialist support particularly post-diagnosis.
Conclusions
There is an extensive body of qualitative literature on the experiences of community-dwelling individuals with dementia on receiving and adapting to a diagnosis of dementia. We present a thematic analysis that could be useful to professionals working with people with dementia. We suggest that research emphasis should shift towards the development and evaluation of interventions, particularly those providing support after diagnosis.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Dementia is a decline in mental ability severe enough to interfere with daily life. Alzheimer disease is the most common type of dementia. People with dementia usually have problems with two or more cognitive functions—thinking, language, memory, understanding, and judgment. Dementia is rare before the age of 65, but about a quarter of people over 85 have dementia. Because more people live longer these days, the number of patients with dementia is increasing. It is estimated that today between 40 and 50 million people live with dementia worldwide. By 2050, this number is expected to triple.
One way to study what dementia means to patients and their carers (most often spouses or other family members) is through qualitative research. Qualitative research aims to develop an in-depth understanding of individuals' experiences and behavior, as well as the reasons for their feelings and actions. In qualitative studies, researchers interview patients, their families, and doctors. When the studies are published, they usually contain direct quotations from interviews as well as summaries by the scientists who designed the interviews and analyzed the responses.
Why Was This Study Done?
This study was done to better understand the experiences and attitudes of patients and their carers surrounding dementia diagnosis. It focused on patients who lived and were cared for within the community (as opposed to people living in senior care facilities or other institutions). Most cases of dementia are progressive, meaning symptoms get worse over time. Diagnosis often happens at an advanced stage of the disease, and some patients never receive a formal diagnosis. This could have many possible reasons, including unawareness or denial of symptoms by patients and people close to them. The study was also trying to understand barriers to early diagnosis and what type of support is useful for newly diagnosed patients and carers.
What Did the Researchers Do and Find?
The researchers conducted a systematic search for published qualitative research studies that reported on the experience, beliefs, feelings, and attitudes surrounding dementia diagnosis. They identified and reviewed 102 such studies. Among the quotations and summaries of the individual studies, they looked for prominent and recurring themes. They also compared and contrasted the respective experiences of patients and carers.
Overall, they found that the complexity and variety of responses to a diagnosis of dementia means that making the diagnosis and conveying it to patients and carers is challenging. Negative connotations associated with dementia, inconsistent symptoms, and not knowing enough about the signs and symptoms were commonly reported barriers to early dementia diagnosis. It was often the carer who initiated the search for help from a doctor, and among patients, willingness and readiness to receive a diagnosis varied. Being told one had dementia had a big impact on a patient's identity and often caused feelings of loss, anger, fear, and frustration. Spouses had to adjust to increasingly unequal relationships and the transition to a role as carer. The strain associated with this often caused health problems in the carers as well. On the other hand, studies examining the experience of couples often reported that they found ways to continue working together as a team.
Adjusting to a dementia diagnosis is a complex process. Initially, most patients and carers experienced conflicts, for example, between autonomy and safety, between recognizing the need for help but reluctance to accept it, or between living in the present and dealing with anxiety about and preparing for the future. As these were resolved and as the disease progressed, the attitudes of patients and carers towards dementia often became more balanced and accepting. Many patients and their families adopted strategies to cope with the impact of dementia on their lives in order to manage the disease and maintain some sort of normal life. These included practical strategies involving reminders, social strategies such as relying on family support, and emotional strategies such as using humor. At some point many patients and carers reported that they were able to adopt positive mindsets and incorporate dementia in their lives.
The studies also pointed to an urgent need for support from outside the family, both right after diagnosis and subsequently. General practitioners and family physicians have important roles in helping patients and carers to get access to information, social and psychological support, and community care. The need for information was reported to be ongoing and varied, and meeting it required a variety of sources and formats. Key needs for patients and carers mentioned in the studies include information on financial aids and entitlements early on, and continued access to supportive professionals and specialists.
What Do These Findings Mean?
Qualitative studies to date on how patients and carers respond to a diagnosis of dementia provide a fairly detailed picture of their experiences. The summary provided here should help professionals to understand better the challenges patients and carers face around the time of diagnosis as well as their immediate and evolving needs. The results also suggest that future research should focus on the development and evaluation of ways to meet those needs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001331.
Wikipedia has pages on dementia and qualitative research (note that Wikipedia is a free online encyclopedia that anyone can edit)
Alzheimer Europe, an umbrella organization of 34 Alzheimer associations from 30 countries across Europe, has a page on the different approaches to research
The UK Department of Health has pages on dementia, including guidelines for carers of people with dementia
MedlinePlus also has information about dementia
doi:10.1371/journal.pmed.1001331
PMCID: PMC3484131  PMID: 23118618
10.  Cognitive reserve, presynaptic proteins and dementia in the elderly 
Translational Psychiatry  2012;2(5):e114-.
Differences in cognitive reserve may contribute to the wide range of likelihood of dementia in people with similar amounts of age-related neuropathology. The amounts and interactions of presynaptic proteins could be molecular components of cognitive reserve, contributing resistance to the expression of pathology as cognitive impairment. We carried out a prospective study with yearly assessments of N=253 participants without dementia at study entry. Six distinct presynaptic proteins, and the protein–protein interaction between synaptosomal-associated protein 25 (SNAP-25) and syntaxin, were measured in post-mortem brains. We assessed the contributions of Alzheimer's disease (AD) pathology, cerebral infarcts and presynaptic proteins to odds of dementia, level of cognitive function and cortical atrophy. Clinical dementia was present in N=97 (38.3%), a pathologic diagnosis of AD in N=142 (56.1%) and cerebral infarcts in N=77 (30.4%). After accounting for AD pathology and infarcts, greater amounts of vesicle-associated membrane protein, complexins I and II and the SNAP-25/syntaxin interaction were associated with lower odds of dementia (odds ratio=0.36–0.68, P<0.001 to P=0.03) and better cognitive function (P<0.001 to P=0.03). Greater cortical atrophy, a putative dementia biomarker, was not associated with AD pathology, but was associated with lower complexin-II (P=0.01) and lower SNAP-25/syntaxin interaction (P<0.001). In conclusion, greater amounts of specific presynaptic proteins and distinct protein–protein interactions may be structural or functional components of cognitive reserve that reduce the risk of dementia with aging.
doi:10.1038/tp.2012.38
PMCID: PMC3365257  PMID: 22832958
Alzheimer's disease; cognitive reserve; complexin; dementia; SNARE protein
11.  Dementia 
Clinical Evidence  2010;2010:1001.
Introduction
Dementia is characterised by chronic, global, non-reversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments on cognitive symptoms of dementia (Alzheimer's, Lewy body, or vascular)? What are the effects of treatments on behavioural and psychological symptoms of dementia (Alzheimer's, Lewy body, or vascular)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 33 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine), antidepressants (clomipramine, fluoxetine, imipramine, sertraline), antipsychotics (haloperidol, olanzapine, quetiapine, risperidone), aromatherapy, benzodiazepines (diazepam, lorazepam), cognitive behavioural therapy (CBT), cognitive stimulation, exercise, ginkgo biloba, memantine, mood stabilisers (carbamazepine, sodium valproate/valproic acid), music therapy, non-steroidal anti-inflammatory drugs (NSAIDs), omega 3 (fish oil), reminiscence therapy, and statins.
Key Points
Dementia is characterised by chronic, global, non-reversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired.
Median life expectancy for people with Alzheimer's and Lewy body dementia is about 6 years after diagnosis, although many people may live far longer.
RCTs of dementia are often not representative of all people with dementia; most are 6 months or less, not in primary care, and most RCTs are in people with Alzheimer's disease. There are fewer RCTs in people with vascular dementia, and fewer still in people with Lewy body dementia.
Cognitive symptoms of dementia can be improved by acetylcholinesterase inhibitors (donepezil, galantamine, and rivastigmine). Acetylcholinesterase inhibitors seem to improve cognitive function, global state, and activities of daily living scores compared with placebo at 26 weeks in people with Alzheimer's disease.However, they may be associated with an increase in adverse effects, particularly GI symptoms (anorexia, nausea, vomiting, or diarrhoea).
We don't know whether cognitive stimulation, music therapy, reminiscence therapy, omega 3 fish oil, statins, or NSAIDs are effective at improving cognitive outcomes in people with cognitive symptoms of dementia, as we found insufficient evidence.
In people with cognitive symptoms, memantine may improve global state and activities of daily living scores in people with moderate to severe Alzheimer's disease over 24 to 28 weeks, but we don't know about these in mild to moderate Alzheimer's disease. Although memantine is associated with a statistically significant increase in cognition scores in some population groups, the clinical importance of these results is unclear.
Ginkgo biloba is unlikely to improve cognitive function in people with Alzheimer's disease or vascular dementia. However, evidence is of poor quality so this conclusion should be interpreted with caution.
Acetylcholinesterase inhibitors may marginally improve neuropsychiatric symptoms compared with placebo in people with behavioural and psychological symptoms of dementia, but they are also associated with adverse effects.
Antidepressants (clomipramine, fluoxetine, imipramine, sertraline) may improve depressive symptoms compared with placebo in people with Alzheimer's disease associated with depression. However, RCTs were small and short term, and adverse effects were sparsely reported.
Memantine may be associated with a small improvement in neuropsychiatric symptoms compared with placebo in people with behavioural and psychological symptoms of dementia, but it is also associated with adverse effects.
We don't know whether diazepam, lorazepam, aromatherapy, CBT, exercise, carbamazepine, or sodium valproate/valproic acid are effective at improving neuropsychiatric symptoms in people with behavioural and psychological symptoms of dementia, as we found insufficient evidence.
Some antipsychotics may improve neuropsychiatric symptoms or aggression in people with behavioural and psychological symptoms of dementia, but antipsychotics are also associated with an increase risk of severe adverse events such as stroke, TIA, or death.
CAUTION: Regulatory bodies have issued alerts that both conventional and atypical antipsychotics are associated with an increased risk of death in elderly people treated for dementia-related psychosis.
PMCID: PMC2907611  PMID: 21726471
12.  Exercise-Induced Cognitive Plasticity, Implications for Mild Cognitive Impairment and Alzheimer’s Disease 
Lifestyle factors such as intellectual stimulation, cognitive and social engagement, nutrition, and various types of exercise appear to reduce the risk for common age-associated disorders such as Alzheimer’s disease (AD) and vascular dementia. In fact, many studies have suggested that promoting physical activity can have a protective effect against cognitive deterioration later in life. Slowing or a deterioration of walking speed is associated with a poor performance in tests assessing psychomotor speed and verbal fluency in elderly individuals. Fitness training influences a wide range of cognitive processes, and the largest positive impact observed is for executive (a.k.a. frontal lobe) functions. Studies show that exercise improves additional cognitive functions such as tasks mediated by the hippocampus, and result in major changes in plasticity in the hippocampus. Interestingly, this exercise-induced plasticity is also pronounced in APOE ε4 carriers who express a risk factor for late-onset AD that may modulate the effect of treatments. Based on AD staging by Braak and Braak (1991) and Braak et al. (1993) we propose that the effects of exercise occur in two temporo-spatial continua of events. The “inward” continuum from isocortex (neocortex) to entorhinal cortex/hippocampus for amyloidosis and a reciprocal “outward” continuum for neurofibrillary alterations. The exercise-induced hypertrophy of the hippocampus at the core of these continua is evaluated in terms of potential for prevention to stave off neuronal degeneration. Exercise-induced production of growth factors such as the brain-derived neurotrophic factor (BDNF) has been shown to enhance neurogenesis and to play a key role in positive cognitive effects. Insulin-like growth factor (IGF-1) may mediate the exercise-induced response to exercise on BDNF, neurogenesis, and cognitive performance. It is also postulated to regulate brain amyloid β (Aβ) levels by increased clearance via the choroid plexus. Growth factors, specifically fibroblast growth factor and IGF-1 receptors and/or their downstream signaling pathways may interact with the Klotho gene which functions as an aging suppressor gene. Neurons may not be the only cells affected by exercise. Glia (astrocytes and microglia), neurovascular units and the Fourth Element may also be affected in a differential fashion by the AD process. Analyses of these factors, as suggested by the multi-dimensional matrix approach, are needed to improve our understanding of this complex multi-factorial process, which is increasingly relevant to conquering the escalating and intersecting world-wide epidemics of dementia, diabetes, and sarcopenia that threaten the global healthcare system. Physical activity and interventions aimed at enhancing and/or mimicking the effects of exercise are likely to play a significant role in mitigating these epidemics, together with the embryonic efforts to develop cognitive rehabilitation for neurodegenerative disorders.
doi:10.3389/fneur.2011.00028
PMCID: PMC3092070  PMID: 21602910
hippocampus; entorhinal cortex; insulin-like growth factor; reduction of systemic inflammation; p38 effector of Aβ-induced neurodegeneration; virtual reality environment; exponentially decreasing risk of cell death; loss of cognitive performance
13.  Caregiver- and Patient-Directed Interventions for Dementia 
Executive Summary
In early August 2007, the Medical Advisory Secretariat began work on the Aging in the Community project, an evidence-based review of the literature surrounding healthy aging in the community. The Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the ministry’s newly released Aging at Home Strategy.
After a broad literature review and consultation with experts, the secretariat identified 4 key areas that strongly predict an elderly person’s transition from independent community living to a long-term care home. Evidence-based analyses have been prepared for each of these 4 areas: falls and fall-related injuries, urinary incontinence, dementia, and social isolation. For the first area, falls and fall-related injuries, an economic model is described in a separate report.
Please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html, to review these titles within the Aging in the Community series.
Aging in the Community: Summary of Evidence-Based Analyses
Prevention of Falls and Fall-Related Injuries in Community-Dwelling Seniors: An Evidence-Based Analysis
Behavioural Interventions for Urinary Incontinence in Community-Dwelling Seniors: An Evidence-Based Analysis
Caregiver- and Patient-Directed Interventions for Dementia: An Evidence-Based Analysis
Social Isolation in Community-Dwelling Seniors: An Evidence-Based Analysis
The Falls/Fractures Economic Model in Ontario Residents Aged 65 Years and Over (FEMOR)
This report features the evidence-based analysis on caregiver- and patient-directed interventions for dementia and is broken down into 4 sections:
Introduction
Caregiver-Directed Interventions for Dementia
Patient-Directed Interventions for Dementia
Economic Analysis of Caregiver- and Patient-Directed Interventions for Dementia
Caregiver-Directed Interventions for Dementia
Objective
To identify interventions that may be effective in supporting the well-being of unpaid caregivers of seniors with dementia living in the community.
Clinical Need: Target Population and Condition
Dementia is a progressive and largely irreversible syndrome that is characterized by a loss of cognitive function severe enough to impact social or occupational functioning. The components of cognitive function affected include memory and learning, attention, concentration and orientation, problem-solving, calculation, language, and geographic orientation. Dementia was identified as one of the key predictors in a senior’s transition from independent community living to admission to a long-term care (LTC) home, in that approximately 90% of individuals diagnosed with dementia will be institutionalized before death. In addition, cognitive decline linked to dementia is one of the most commonly cited reasons for institutionalization.
Prevalence estimates of dementia in the Ontario population have largely been extrapolated from the Canadian Study of Health and Aging conducted in 1991. Based on these estimates, it is projected that there will be approximately 165,000 dementia cases in Ontario in the year 2008, and by 2010 the number of cases will increase by nearly 17% over 2005 levels. By 2020 the number of cases is expected to increase by nearly 55%, due to a rise in the number of people in the age categories with the highest prevalence (85+). With the increase in the aging population, dementia will continue to have a significant economic impact on the Canadian health care system. In 1991, the total costs associated with dementia in Canada were $3.9 billion (Cdn) with $2.18 billion coming from LTC.
Caregivers play a crucial role in the management of individuals with dementia because of the high level of dependency and morbidity associated with the condition. It has been documented that a greater demand is faced by dementia caregivers compared with caregivers of persons with other chronic diseases. The increased burden of caregiving contributes to a host of chronic health problems seen among many informal caregivers of persons with dementia. Much of this burden results from managing the behavioural and psychological symptoms of dementia (BPSD), which have been established as a predictor of institutionalization for elderly patients with dementia.
It is recognized that for some patients with dementia, an LTC facility can provide the most appropriate care; however, many patients move into LTC unnecessarily. For individuals with dementia to remain in the community longer, caregivers require many types of formal and informal support services to alleviate the stress of caregiving. These include both respite care and psychosocial interventions. Psychosocial interventions encompass a broad range of interventions such as psychoeducational interventions, counseling, supportive therapy, and behavioural interventions.
Assuming that 50% of persons with dementia live in the community, a conservative estimate of the number of informal caregivers in Ontario is 82,500. Accounting for the fact that 29% of people with dementia live alone, this leaves a remaining estimate of 58,575 Ontarians providing care for a person with dementia with whom they reside.
Description of Interventions
The 2 main categories of caregiver-directed interventions examined in this review are respite care and psychosocial interventions. Respite care is defined as a break or relief for the caregiver. In most cases, respite is provided in the home, through day programs, or at institutions (usually 30 days or less). Depending on a caregiver’s needs, respite services will vary in delivery and duration. Respite care is carried out by a variety of individuals, including paid staff, volunteers, family, or friends.
Psychosocial interventions encompass a broad range of interventions and have been classified in various ways in the literature. This review will examine educational, behavioural, dementia-specific, supportive, and coping interventions. The analysis focuses on behavioural interventions, that is, those designed to help the caregiver manage BPSD. As described earlier, BPSD are one of the most challenging aspects of caring for a senior with dementia, causing an increase in caregiver burden. The analysis also examines multicomponent interventions, which include at least 2 of the above-mentioned interventions.
Methods of Evidence-Based Analysis
A comprehensive search strategy was used to identify systematic reviews and randomized controlled trials (RCTs) that examined the effectiveness of interventions for caregivers of dementia patients.
Questions
Section 2.1
Are respite care services effective in supporting the well-being of unpaid caregivers of seniors with dementia in the community?
Do respite care services impact on rates of institutionalization of these seniors?
Section 2.2
Which psychosocial interventions are effective in supporting the well-being of unpaid caregivers of seniors with dementia in the community?
Which interventions reduce the risk for institutionalization of seniors with dementia?
Outcomes of Interest
any quantitative measure of caregiver psychological health, including caregiver burden, depression, quality of life, well-being, strain, mastery (taking control of one’s situation), reactivity to behaviour problems, etc.;
rate of institutionalization; and
cost-effectiveness.
Assessment of Quality of Evidence
The quality of the evidence was assessed as High, Moderate, Low, or Very low according to the GRADE methodology and GRADE Working Group. As per GRADE the following definitions apply:
Summary of Findings
Conclusions in Table 1 are drawn from Sections 2.1 and 2.2 of the report.
Summary of Conclusions on Caregiver-Directed Interventions
There is limited evidence from RCTs that respite care is effective in improving outcomes for those caring for seniors with dementia.
There is considerable qualitative evidence of the perceived benefits of respite care.
Respite care is known as one of the key formal support services for alleviating caregiver burden in those caring for dementia patients.
Respite care services need to be tailored to individual caregiver needs as there are vast differences among caregivers and patients with dementia (severity, type of dementia, amount of informal/formal support available, housing situation, etc.)
There is moderate- to high-quality evidence that individual behavioural interventions (≥ 6 sessions), directed towards the caregiver (or combined with the patient) are effective in improving psychological health in dementia caregivers.
There is moderate- to high-quality evidence that multicomponent interventions improve caregiver psychosocial health and may affect rates of institutionalization of dementia patients.
RCT indicates randomized controlled trial.
Patient-Directed Interventions for Dementia
Objective
The section on patient-directed interventions for dementia is broken down into 4 subsections with the following questions:
3.1 Physical Exercise for Seniors with Dementia – Secondary Prevention
What is the effectiveness of physical exercise for the improvement or maintenance of basic activities of daily living (ADLs), such as eating, bathing, toileting, and functional ability, in seniors with mild to moderate dementia?
3.2 Nonpharmacologic and Nonexercise Interventions to Improve Cognitive Functioning in Seniors With Dementia – Secondary Prevention
What is the effectiveness of nonpharmacologic interventions to improve cognitive functioning in seniors with mild to moderate dementia?
3.3 Physical Exercise for Delaying the Onset of Dementia – Primary Prevention
Can exercise decrease the risk of subsequent cognitive decline/dementia?
3.4 Cognitive Interventions for Delaying the Onset of Dementia – Primary Prevention
Does cognitive training decrease the risk of cognitive impairment, deterioration in the performance of basic ADLs or instrumental activities of daily living (IADLs),1 or incidence of dementia in seniors with good cognitive and physical functioning?
Clinical Need: Target Population and Condition
Secondary Prevention2
Exercise
Physical deterioration is linked to dementia. This is thought to be due to reduced muscle mass leading to decreased activity levels and muscle atrophy, increasing the potential for unsafe mobility while performing basic ADLs such as eating, bathing, toileting, and functional ability.
Improved physical conditioning for seniors with dementia may extend their independent mobility and maintain performance of ADL.
Nonpharmacologic and Nonexercise Interventions
Cognitive impairments, including memory problems, are a defining feature of dementia. These impairments can lead to anxiety, depression, and withdrawal from activities. The impact of these cognitive problems on daily activities increases pressure on caregivers.
Cognitive interventions aim to improve these impairments in people with mild to moderate dementia.
Primary Prevention3
Exercise
Various vascular risk factors have been found to contribute to the development of dementia (e.g., hypertension, hypercholesterolemia, diabetes, overweight).
Physical exercise is important in promoting overall and vascular health. However, it is unclear whether physical exercise can decrease the risk of cognitive decline/dementia.
Nonpharmacologic and Nonexercise Interventions
Having more years of education (i.e., a higher cognitive reserve) is associated with a lower prevalence of dementia in crossectional population-based studies and a lower incidence of dementia in cohorts followed longitudinally. However, it is unclear whether cognitive training can increase cognitive reserve or decrease the risk of cognitive impairment, prevent or delay deterioration in the performance of ADLs or IADLs or reduce the incidence of dementia.
Description of Interventions
Physical exercise and nonpharmacologic/nonexercise interventions (e.g., cognitive training) for the primary and secondary prevention of dementia are assessed in this review.
Evidence-Based Analysis Methods
A comprehensive search strategy was used to identify systematic reviews and RCTs that examined the effectiveness, safety and cost effectiveness of exercise and cognitive interventions for the primary and secondary prevention of dementia.
Questions
Section 3.1: What is the effectiveness of physical exercise for the improvement or maintenance of ADLs in seniors with mild to moderate dementia?
Section 3.2: What is the effectiveness of nonpharmacologic/nonexercise interventions to improve cognitive functioning in seniors with mild to moderate dementia?
Section 3.3: Can exercise decrease the risk of subsequent cognitive decline/dementia?
Section 3.4: Does cognitive training decrease the risk of cognitive impairment, prevent or delay deterioration in the performance of ADLs or IADLs, or reduce the incidence of dementia in seniors with good cognitive and physical functioning?
Assessment of Quality of Evidence
The quality of the evidence was assessed as High, Moderate, Low, or Very low according to the GRADE methodology. As per GRADE the following definitions apply:
Summary of Findings
Table 2 summarizes the conclusions from Sections 3.1 through 3.4.
Summary of Conclusions on Patient-Directed Interventions*
Previous systematic review indicated that “cognitive training” is not effective in patients with dementia.
A recent RCT suggests that CST (up to 7 weeks) is effective for improving cognitive function and quality of life in patients with dementia.
Regular leisure time physical activity in midlife is associated with a reduced risk of dementia in later life (mean follow-up 21 years).
Regular physical activity in seniors is associated with a reduced risk of cognitive decline (mean follow-up 2 years).
Regular physical activity in seniors is associated with a reduced risk of dementia (mean follow-up 6–7 years).
Evidence that cognitive training for specific functions (memory, reasoning, and speed of processing) produces improvements in these specific domains.
Limited inconclusive evidence that cognitive training can offset deterioration in the performance of self-reported IADL scores and performance assessments.
1° indicates primary; 2°, secondary; CST, cognitive stimulation therapy; IADL, instrumental activities of daily living; RCT, randomized controlled trial.
Benefit/Risk Analysis
As per the GRADE Working Group, the overall recommendations consider 4 main factors:
the trade-offs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates, and the relative value placed on the outcome;
the quality of the evidence;
translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects such as proximity to a hospital or availability of necessary expertise; and
uncertainty about the baseline risk for the population of interest.
The GRADE Working Group also recommends that incremental costs of health care alternatives should be considered explicitly alongside the expected health benefits and harms. Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 3 reflects the overall trade-off between benefits and harms (adverse events) and incorporates any risk/uncertainty (cost-effectiveness).
Overall Summary Statement of the Benefit and Risk for Patient-Directed Interventions*
Economic Analysis
Budget Impact Analysis of Effective Interventions for Dementia
Caregiver-directed behavioural techniques and patient-directed exercise programs were found to be effective when assessing mild to moderate dementia outcomes in seniors living in the community. Therefore, an annual budget impact was calculated based on eligible seniors in the community with mild and moderate dementia and their respective caregivers who were willing to participate in interventional home sessions. Table 4 describes the annual budget impact for these interventions.
Annual Budget Impact (2008 Canadian Dollars)
Assumed 7% prevalence of dementia aged 65+ in Ontario.
Assumed 8 weekly sessions plus 4 monthly phone calls.
Assumed 12 weekly sessions plus biweekly sessions thereafter (total of 20).
Assumed 2 sessions per week for first 5 weeks. Assumed 90% of seniors in the community with dementia have mild to moderate disease. Assumed 4.5% of seniors 65+ are in long-term care, and the remainder are in the community. Assumed a rate of participation of 60% for both patients and caregivers and of 41% for patient-directed exercise. Assumed 100% compliance since intervention administered at the home. Cost for trained staff from Ministry of Health and Long-Term Care data source. Assumed cost of personal support worker to be equivalent to in-home support. Cost for recreation therapist from Alberta government Website.
Note: This budget impact analysis was calculated for the first year after introducing the interventions from the Ministry of Health and Long-Term Care perspective using prevalence data only. Prevalence estimates are for seniors in the community with mild to moderate dementia and their respective caregivers who are willing to participate in an interventional session administered at the home setting. Incidence and mortality rates were not factored in. Current expenditures in the province are unknown and therefore were not included in the analysis. Numbers may change based on population trends, rate of intervention uptake, trends in current programs in place in the province, and assumptions on costs. The number of patients was based on patients likely to access these interventions in Ontario based on assumptions stated below from the literature. An expert panel confirmed resource consumption.
PMCID: PMC3377513  PMID: 23074509
14.  Pathology and pathogenesis of vascular cognitive impairment—a critical update 
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.
doi:10.3389/fnagi.2013.00017
PMCID: PMC3622231  PMID: 23596414
vascular dementia; vascular cognitive impairment; cerebral infarcts; large and small vessel disease; subcortical vascular lesions; neuropathology; pathogenic factors
15.  Dementia prevention: current epidemiological evidence and future perspective 
Dementia, a major cause of disability and institutionalization in older people, poses a serious threat to public health and to the social and economic development of modern society. Alzheimer's disease (AD) and cerebrovascular diseases are the main causes of dementia; most dementia cases are attributable to both vascular and neurodegenerative brain damage. No curative treatment is available, but epidemiological research provides a substantial amount of evidence of modifiable risk and protective factors that can be addressed to prevent or delay onset of AD and dementia. Risk of late-life dementia is determined by exposures to multiple factors experienced over the life course, and the effect of specific risk/protective factors depends largely on age. Moreover, cumulative and combined exposure to different risk/protective factors can modify their effect on dementia/AD risk. Multidisciplinary research involving epidemiology, neuropathology, and neuroimaging has provided sufficient evidence that vascular risk factors significantly contribute to the expression and progression of cognitive decline (including dementia) but that active engagement in social, physical, and mentally stimulating activities may delay the onset of dementia. However, these findings need to be confirmed by randomized controlled trials (RCTs). A promising strategy for preventing dementia is to implement intervention programs that take into account both the life-course model and the multifactorial nature of this syndrome. In Europe, there are three ongoing multidomain interventional RCTs that focus on the optimal management of vascular risk factors and vascular diseases. The RCTs include medical and lifestyle interventions and promote social, mental, and physical activities aimed at increasing the cognitive reserve. These studies will provide new insights into prevention of cognitive impairment and dementia. Such knowledge can help researchers plan larger, international prevention trials that could provide robust evidence on dementia/AD prevention. Taking a step in this direction, researchers involved in these European RCTs recently started the European Dementia Prevention Initiative, an international collaboration aiming to improve strategies for preventing dementia.
doi:10.1186/alzrt104
PMCID: PMC3471409  PMID: 22339927
16.  Alzheimer disease identification using amyloid imaging and reserve variables 
Neurology  2010;75(1):42-48.
Objective:
Several factors may influence the relationship between Alzheimer disease (AD) lesions and the expression of dementia, including those related to brain and cognitive reserve. Other factors may confound the association between AD pathology and dementia. We tested whether factors thought to influence the association of AD pathology and dementia help to accurately identify dementia of the Alzheimer type (DAT) when considered together with amyloid imaging.
Methods:
Participants with normal cognition (n = 180) and with DAT (n = 25), aged 50 years or older, took part in clinical, neurologic, and psychometric assessments. PET with the Pittsburgh compound B (PiB) tracer was used to measure brain amyloid, yielding a mean cortical binding potential (MCBP) reflecting PiB uptake. Logistic regression was used to generate receiver operating characteristic curves, and the areas under those curves (AUC), to compare the predictive accuracy of using MCBP alone vs MCBP together with other variables selected using a stepwise selection procedure to identify participants with DAT vs normal cognition.
Results:
The AUC resulting from MCBP alone was 0.84 (95% confidence interval [CI] = 0.73–0.94; cross-validated AUC = 0.80, 95% CI = 0.68–0.92). The AUC for the predictive equation generated by a stepwise model including education, normalized whole brain volume, physical health rating, gender, and use of medications that may interfere with cognition was 0.94 (95% CI = 0.90–0.98; cross-validated AUC = 0.91, 95% CI = 0.85–0.96), an improvement (p = 0.025) over that yielded using MCBP alone.
Conclusion:
Results suggest that factors reported to influence associations between AD pathology and dementia can improve the predictive accuracy of amyloid imaging for the identification of symptomatic AD.
GLOSSARY
β = amyloid-β;
= Alzheimer disease;
= area under receiver operating characteristic curve;
= binding potential;
= Clinical Dementia Rating;
= confidence interval;
= dementia of the Alzheimer type;
= distribution volume;
= mean cortical binding potential;
= normalized whole brain volume;
= odds ratio;
= Pittsburgh compound B;
= receiver operating characteristic curve;
= region of interest.
doi:10.1212/WNL.0b013e3181e620f4
PMCID: PMC2906402  PMID: 20603484
17.  Cognitive Activities During Adulthood Are More Important than Education in Building Reserve 
Cognitive reserve is thought to reflect life experiences. Which experiences contribute to reserve and their relative importance is not understood. Subjects were 652 autopsied cases from the Rush Memory and Aging Project and the Religious Orders Study. Reserve was defined as the residual variance of the regressions of cognitive factors on brain pathology and was captured in a latent variable that was regressed on potential determinants of reserve. Neuropathology variables included Alzheimer’s disease markers, Lewy bodies, infarcts, microinfarcts, and brain weight. Cognition was measured with six cognitive domain scores. Determinants of reserve were socioeconomic status (SES), education, leisure cognitive activities at age 40 (CA40) and at study enrollment (CAbaseline) in late life. The four exogenous predictors of reserve were weakly to moderately inter-correlated. In a multivariate model, all except SES had statistically significant effects on Reserve, the strongest of which were CA40 (β= .31) and CAbaseline (β= .28). The Education effect was negative in the full model (β= −.25). Results suggest that leisure cognitive activities throughout adulthood are more important than education in determining reserve. Discrepancies between cognitive activity and education may be informative in estimating late life reserve.
doi:10.1017/S1355617711000014
PMCID: PMC3498078  PMID: 23131600
Cognitive reserve; Alzheimer’s disease; Cerebrovascular disorders; Aging; Neuropsychological test battery; Multivariate analysis
18.  Measuring cognitive reserve based on the decomposition of episodic memory variance 
Brain  2010;133(8):2196-2209.
In later adulthood brain pathology becomes common and trajectories of cognitive change are heterogeneous. Among the multiple determinants of late-life cognitive course, cognitive reserve has been proposed as an important factor that modifies or buffers the impact of brain pathology on cognitive function. This article presents and investigates a novel method for measuring and investigating such factors. The core concept is that in a population where pathology is common and variably present, ‘reserve’ may be defined as the difference between the cognitive performance predicted by an individual's level of pathology and that individual's actual performance. By this definition, people whose measured cognitive performance is better than predicted by pathology have high reserve, whereas those who perform worse than predicted have low reserve. To test this hypothesis, we applied a latent variable model to data from a diverse ageing cohort and decomposed the variance in a measure of episodic memory into three components, one predicted by demographics, one predicted by pathology as measured by structural MRI and a ‘residual’ or ‘reserve’ term that included all remaining variance. To investigate the plausibility of this approach, we then tested the residual component as an operational measure of reserve. Specific predictions about the effects of this putative reserve measure were generated from a general conceptual model of reserve. Each was borne from the results. The results show that the current level of reserve, as measured by this decomposition approach, modifies rates of conversion from mild cognitive impairment to dementia, modifies rates of longitudinal decline in executive function and, most importantly, attenuates the effect of brain atrophy on cognitive decline such that atrophy is more strongly associated with cognitive decline in subjects with low reserve than in those with high reserve. Decomposing the variance in cognitive function scores offers a promising new approach to the measure and study of cognitive reserve.
doi:10.1093/brain/awq154
PMCID: PMC3139935  PMID: 20591858
cognitive ageing; mild cognitive impairment; dementia; neuropsychological tests; longitudinal change; cognitive reserve
19.  Brain Networks Associated with Cognitive Reserve in Healthy Young and Old Adults 
In order to understand the brain networks that mediate cognitive reserve, we explored the relationship between subjects’ network expression during the performance of a memory test and an index of cognitive reserve. Using H215O positron emission tomography, we imaged 17 healthy older subjects and 20 young adults while they performed a serial recognition memory task for nonsense shapes under two conditions: low demand, with a unique shape presented in each study trial; and titrated demand, with a study list size adjusted so that each subject recognized shapes at 75% accuracy. A factor score that summarized years of education, and scores on the NART and the WAIS-R Vocabulary subtest was used as an index of cognitive reserve. The scaled subprofile model was used to identify a set of functionally connected regions (or topography) that changed in expression across the two task conditions and was differentially expressed by the young and elderly subjects. The regions most active in this topography consisted of right hippocampus, posterior insula, thalamus, and right and left operculum; we found concomitant deactivation in right lingual gyrus, inferior parietal lobe and association cortex, left posterior cingulate, and right and left calcarine cortex. Young subjects with higher cognitive reserve showed increased expression of the topography across the two task conditions. Because this topography, which is responsive to increased task demands, was differentially expressed as a function of reserve level, it may represent a neural manifestation of innate or acquired reserve. In contrast, older subjects with higher cognitive reserve showed decreased expression of the topography across tasks. This suggests some functional reorganization of the network used by the young subjects. Thus, for the old subjects this topography may represent an altered, compensatory network that is used to maintain function in the face of age-related physiological changes.
doi:10.1093/cercor/bhh142
PMCID: PMC3025536  PMID: 15749983
compensation; covariance analysis; education; H215O PET; IQ
20.  Cognitive Decline and Dementia in the Oldest-Old 
The oldest-old are the fastest growing segment of the Western population. Over half of the oldest-old will have dementia, but the etiology is yet unknown. Age is the only risk factor consistently associated with dementia in the oldest-old. Many of the risk and protective factors for dementia in the young elderly, such as ApoE genotype, physical activity, and healthy lifestyle, are not relevant for the oldest-old. Neuropathology is abundant in the oldest-old brains, but specific pathologies of Alzheimer’s disease (AD) or vascular dementia are not necessarily correlated with cognition, as in younger persons. It has been suggested that accumulation of both AD-like and vascular pathologies, loss of synaptic proteins, and neuronal loss contribute to the cognitive decline observed in the oldest-old. Several characteristics of the oldest-old may confound the diagnosis of dementia in this age group. A gradual age-related cognitive decline, particularly in executive function and mental speed, is evident even in non-demented oldest-old. Hearing and vision losses, which are also prevalent in the oldest-old and found in some cases to precede/predict cognitive decline, may mechanically interfere in neuropsychological evaluations. Difficulties in carrying out everyday activities, observed in the majority of the oldest-old, may be the result of motor or physical dysfunction and of neurodegenerative processes. The oldest-old appear to be a select population, who escapes major illnesses or delays their onset and duration toward the end of life. Dementia in the oldest-old may be manifested when a substantial amount of pathology is accumulated, or with a composition of a variety of pathologies. Investigating the clinical and pathological features of dementia in the oldest-old is of great importance in order to develop therapeutic strategies and to provide the most elderly of our population with good quality of life.
doi:10.5041/RMMJ.10092
PMCID: PMC3678827  PMID: 23908850
Dementia; epidemiology; neurobiology; oldest-old; risk factors
21.  Stroke Prevention and Cognitive Reserve: Emerging Approaches to Modifying Risk and Delaying Onset of Dementia 
Demographic changes and improvements in health care are projected to result in dramatic increases in the prevalence of dementia. Alzheimer’s disease is widely considered to be the primary cause of dementia – a disease for which there is currently no cure nor effective treatment, and for which it is thought that little can be done to mitigate risk. However, an increasing understanding of the role and extent of vascular contributions to the development of dementia, and appreciation of the interactions between stroke and Alzheimer’s disease, suggest that targeting vascular risk factors may be very beneficial in reducing the impact of dementia. We also describe how active stimulation of the brain throughout the life course builds cognitive reserve that can offset or compensate for cognitive decline in later life. Finally, we discuss the implications of these emerging approaches for dementia prevention and advocate for the urgent implementation of more extensive public health strategies to improve vascular health.
doi:10.3389/fneur.2013.00013
PMCID: PMC3604564  PMID: 23518689
stroke; Alzheimer’s; prevention; cognitive reserve; dementia
22.  Vascular Contributions to Cognitive Impairment and Dementia 
Background and Purpose
This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment and dementia of later life are common. Definitions of vascular cognitive impairment (VCI), neuropathology, basic science and pathophysiological aspects, role of neuroimaging and vascular and other associated risk factors, and potential opportunities for prevention and treatment are reviewed. This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment.
Methods
Writing group members were nominated by the writing group co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council Scientific Statement Oversight Committee, the Council on Epidemiology and Prevention, and the Manuscript Oversight Committee. The writing group used systematic literature reviews (primarily covering publications from 1990 to May 1, 2010), previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. After peer review by the American Heart Association, as well as review by the Stroke Council leadership, Council on Epidemiology and Prevention Council, and Scientific Statements Oversight Committee, the statement was approved by the American Heart Association Science Advisory and Coordinating Committee.
Results
The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury—not solely stroke—ranging from mild cognitive impairment through fully developed dementia. Dysfunction of the neurovascular unit and mechanisms regulating cerebral blood flow are likely to be important components of the pathophysiological processes underlying VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage of the brain, and VCI. The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment. In this regard, magnetic resonance imaging and other neuroimaging techniques play an important role in the definition and detection of VCI and provide evidence that subcortical forms of VCI with white matter hyperintensities and small deep infarcts are common. In many cases, risk markers for VCI are the same as traditional risk factors for stroke. These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease. Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI. Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration. However, detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of VCI, even in older people.
Conclusions
Vascular contributions to cognitive impairment and dementia are important. Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies. Transdisciplinary, translational, and transactional approaches are recommended to further our understanding of this entity and to better characterize its neuropsychological profile. There is a need for prospective, quantitative, clinical-pathological-neuroimaging studies to improve knowledge of the pathological basis of neuroimaging change and the complex interplay between vascular and Alzheimer disease pathologies in the evolution of clinical VCI and Alzheimer disease. Long-term vascular risk marker interventional studies beginning as early as midlife may be required to prevent or postpone the onset of VCI and Alzheimer disease. Studies of intensive reduction of vascular risk factors in high-risk groups are another important avenue of research.
doi:10.1161/STR.0b013e3182299496
PMCID: PMC3778669  PMID: 21778438
AHA Scientific Statements; vascular dementia; Alzheimer disease; risk factors; prevention; treatment
23.  Cholinesterase Inhibitors in Mild Cognitive Impairment: A Systematic Review of Randomised Trials 
PLoS Medicine  2007;4(11):e338.
Background
Mild cognitive impairment (MCI) refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs) currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD), in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine) in delaying the conversion from MCI to Alzheimer disease or dementia.
Methods and Findings
The terms “donepezil”, “rivastigmine”, “galantamine”, and “mild cognitive impairment” and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO) and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and ClinicalTrials.gov. Published and unpublished studies were included if they were randomized clinical trials published (or described) in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine). Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y) to 25% (over 3 y) among treated patients, and from 18% (over 2 y) to 28% (over 3 y) among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of conversion: 0.85 (95% confidence interval 0.64–1.12), and 0.84 (0.57–1.25). Statistically significant differences emerged for three secondary end points. However, when adjusting for multiple comparisons, only one difference remained significant (i.e., the rate of atrophy in the whole brain).
Conclusions
The use of ChEIs in MCI was not associated with any delay in the onset of AD or dementia. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible. The uncertainty regarding MCI as a clinical entity raises the question as to the scientific validity of these trials.
A systematic review of trials of cholinesterase inhibitors for preventing transition of mild cognitive impairment (MCI) to dementia, conducted by Roberto Raschetti and colleagues, found no difference between treatment and control groups and concluded that uncertainty regarding the definition of MCI casts doubts on the validity of such trials.
Editors' Summary
Background.
Worldwide, more than 24 million people have dementia, a group of brain disorders characterized by an irreversible decline in memory, problem solving, communication, and other “cognitive” functions. The commonest form of dementia is Alzheimer disease (AD). The risk of developing AD increases with age—AD is rare in people younger than 65 but about half of people over 85 years old have it. The earliest symptom of AD is usually difficulty in remembering new information. As the disease progresses, patients may become confused and have problems expressing themselves. Their behavior and personality can also change. In advanced AD, patients need help with daily activities like dressing and eating, and eventually lose their ability to recognize relatives and to communicate. There is no cure for AD but a class of drugs called “cholinesterase inhibitors” can sometimes temporarily slow the worsening of symptoms. Three cholinesterase inhibitors—donepezil, rivastigmine, and galantamine—are currently approved for use in mild-to-moderate AD.
Why Was This Study Done?
Some experts have questioned the efficacy of cholinesterase inhibitors in AD, but other experts and patient support groups have called for these drugs to be given to patients with a condition called mild cognitive impairment (MCI) as well as to those with mild AD. People with MCI have memory problems that are more severe than those normally seen in people of their age but no other symptoms of dementia. They are thought to have an increased risk of developing AD, but it is not known whether everyone with MCI eventually develops AD, and there is no standardized way to diagnose MCI. Despite these uncertainties, several clinical trials have investigated whether cholinesterase inhibitors prevent progression from MCI to AD. In this study, the researchers have assessed whether the results of these trials provide any evidence that cholinesterase inhibitors can prevent MCI progressing to AD.
What Did the Researchers Do and Find?
The researchers conducted a systematic review of the medical literature to find trials that had addressed this issue, which met criteria that they had defined clearly in advance of their search. They identified three published and five unpublished randomized controlled trials (studies in which patients randomly receive the test drug or an inactive placebo) that investigated the effect of cholinesterase inhibitors on the progression of MCI. The researchers obtained the results of six of these trials—four examined the effect of cholinesterase inhibitors on the conversion of MCI to clinically diagnosed AD or dementia (the primary end point); all six examined the effect of the drugs on several secondary end points (for example, individual aspects of cognitive function). None of the drugs produced a statistically significant difference (a difference that is unlikely to have happened by chance) in the probability of progression from MCI to AD. The only statistically significant secondary end point after adjustment for multiple comparisons (when many outcomes are considered, false positive results can occur unless specific mathematical techniques are used to prevent this problem) was a decrease in the rate of brain shrinkage associated with galantamine treatment. More patients treated with cholinesterase inhibitors dropped out of trials because of adverse effects than patients given placebo. Finally, in the one trial that reported all causes of deaths, one participant who received placebo and six who received galantamine died.
What Do These Findings Mean?
These findings suggest that the use of cholinesterase inhibitors is not associated with any delay in the onset of clinically diagnosed AD or dementia in people with MCI. They also show that the use of these drugs has no effect on most surrogate (substitute) indicators of AD but that the risks associated with their use are not negligible. However, because MCI has not yet been clearly defined as a clinical condition that precedes dementia, some (even many) of the patients enrolled into the trials that the researchers assessed may not actually have had MCI. Thus, further clinical trials are needed to clarify whether cholinesterase inhibitors can delay the progression of MCI to dementia, but these additional trials should not be done until the diagnosis of MCI has been standardized.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040338.
An essay by Matthews and colleagues, in the October 2007 issue of PLoS Medicine, discusses how mild cognitive impairment is currently diagnosed
The US Alzheimer's Association provides information about all aspects of Alzheimer disease, including fact sheets on treatments for Alzheimer disease and on mild cognitive impairment
The UK Alzheimer's Society provides information for patients and caregivers on all aspects of dementia, including drug treatments and mild cognitive impairment
The UK charity DIPEx provides short video clips of personal experiences of care givers of people with dementia
doi:10.1371/journal.pmed.0040338
PMCID: PMC2082649  PMID: 18044984
24.  Dementia in the oldest old: a multi-factorial and growing public health issue 
The population of oldest old, or people aged 85 and older, is growing rapidly. A better understanding of dementia in this population is thus of increasing national and global importance. In this review, we describe the major epidemiological studies, prevalence, clinical presentation, neuropathological and imaging features, risk factors, and treatment of dementia in the oldest old. Prevalence estimates for dementia among those aged 85+ ranges from 18 to 38%. The most common clinical syndromes are Alzheimer's dementia, vascular dementia, and mixed dementia from multiple etiologies. The rate of progression appears to be slower than in the younger old. Single neuropathological entities such as Alzheimer's dementia and Lewy body pathology appear to have declining relevance to cognitive decline, while mixed pathology with Alzheimer's disease, vascular disease (especially cortical microinfarcts), and hippocampal sclerosis appear to have increasing relevance. Neuroimaging data are sparse. Risk factors for dementia in the oldest old include a low level of education, poor mid-life general health, low level of physical activity, depression, and delirium, whereas apolipoprotein E genotype, late-life hypertension, hyperlipidemia, and elevated peripheral inflammatory markers appear to have less relevance. Treatment approaches require further study, but the oldest old may be more prone to negative side effects compared with younger patients and targeted therapies may be less efficacious since single pathologies are less frequent. We also highlight the limitations and challenges of research in this area, including the difficulty of defining functional decline, a necessary component for a dementia diagnosis, the lack of normative neuropsychological data, and other shortcomings inherent in existing diagnostic criteria. In summary, our understanding of dementia in the oldest old has advanced dramatically in recent years, but more research is needed, particularly among varied racial, ethnic, and socioeconomic groups, and with respect to biomarkers such as neuroimaging, modifiable risk factors, and therapy.
doi:10.1186/alzrt181
PMCID: PMC3706944  PMID: 23809176
25.  Cognitive Reserve: Implications for Diagnosis and Prevention of Alzheimer's Disease 
Epidemiologic evidence suggests that higher occupational attainment and education, as well as increased participation in intellectual, social, and physical aspects of daily life, are associated with slower cognitive decline in healthy elderly and may reduce the risk of incident Alzheimer's disease (AD). There is also evidence from structural and functional imaging studies that patients with such life experiences can tolerate more AD pathology before showing signs of clinical dementia. It has been hypothesized that such aspects of life experience may result in functionally more efficient cognitive networks and, therefore, provide a cognitive reserve that delays the onset of clinical manifestations of dementia. In this article, we review some of the relevant literature of the noted associations between markers of cognitive reserve and AD and discuss the possible mechanisms that may explain these associations.
PMCID: PMC3026565  PMID: 15324603

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