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1.  First Diagnosis and Management of Incontinence in Older People with and without Dementia in Primary Care: A Cohort Study Using The Health Improvement Network Primary Care Database 
PLoS Medicine  2013;10(8):e1001505.
Robert Grant and colleagues used the British THIN primary care database to determine rates of first diagnosis of urinary and faecal incontinence among people aged 60–89 with dementia compared with those without dementia, and the use of medication or indwelling catheters for urinary incontinence in those with and without dementia.
Please see later in the article for the Editors' Summary
Background
Dementia is one of the most disabling and burdensome diseases. Incontinence in people with dementia is distressing, adds to carer burden, and influences decisions to relocate people to care homes. Successful and safe management of incontinence in people with dementia presents additional challenges. The aim of this study was to investigate the rates of first diagnosis in primary care of urinary and faecal incontinence among people aged 60–89 with dementia, and the use of medication or indwelling catheters for urinary incontinence.
Methods and Findings
We extracted data on 54,816 people aged 60–89 with dementia and an age-gender stratified sample of 205,795 people without dementia from 2001 to 2010 from The Health Improvement Network (THIN), a United Kingdom primary care database. THIN includes data on patients and primary care consultations but does not identify care home residents. Rate ratios were adjusted for age, sex, and co-morbidity using multilevel Poisson regression.
The rates of first diagnosis per 1,000 person-years at risk (95% confidence interval) for urinary incontinence in the dementia cohort, among men and women, respectively, were 42.3 (40.9–43.8) and 33.5 (32.6–34.5). In the non-dementia cohort, the rates were 19.8 (19.4–20.3) and 18.6 (18.2–18.9). The rates of first diagnosis for faecal incontinence in the dementia cohort were 11.1 (10.4–11.9) and 10.1 (9.6–10.6). In the non-dementia cohort, the rates were 3.1 (2.9–3.3) and 3.6 (3.5–3.8).
The adjusted rate ratio for first diagnosis of urinary incontinence was 3.2 (2.7–3.7) in men and 2.7 (2.3–3.2) in women, and for faecal incontinence was 6.0 (5.1–7.0) in men and 4.5 (3.8–5.2) in women. The adjusted rate ratio for pharmacological treatment of urinary incontinence was 2.2 (1.4–3.7) for both genders, and for indwelling urinary catheters was 1.6 (1.3–1.9) in men and 2.3 (1.9–2.8) in women.
Conclusions
Compared with those without a dementia diagnosis, those with a dementia diagnosis have approximately three times the rate of diagnosis of urinary incontinence, and more than four times the rate of faecal incontinence, in UK primary care. The clinical management of urinary incontinence in people with dementia with medication and particularly the increased use of catheters is concerning and requires further investigation.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, more than 35 million people have dementia, brain disorders that are characterized by an irreversible decline in cognitive functions such as language and memory. Alzheimer's disease and other forms of dementia mainly affect older people and, because people are living longer than ever, experts estimate that by 2050 more than 115 million people will have dementia. The earliest sign of dementia is usually increasing forgetfulness but, as the disease progresses, people gradually lose their ability to deal with normal daily activities such as dressing, they may become anxious or aggressive, and they may lose control of their bladder (urinary incontinence), bowels (bowel or fecal incontinence), and other physical functions. As a result, people with dementia require increasing amounts of care as the disease progresses. Relatives and other unpaid carers provide much of this care—two-thirds of people with dementia are cared for at home. However, many people with dementia end their days in a care or nursing home.
Why Was This Study Done?
Incontinence in people with dementia is distressing for the person with dementia and for their carers and often influences decisions to move individuals into care homes. However, little is known about the diagnosis and treatment of urinary and/or fecal incontinence among people with dementia living at home. This information is needed to help policymakers commission the services required for this section of society and insurers recognize the needs such patients have, as well as helping to raise clinicians' awareness of the issue. In this cohort study (an investigation that compares outcomes in groups of people with different characteristics), the researchers use data routinely collected from general practices (primary care) in the UK to determine the rate of first diagnosis of urinary and fecal incontinence in elderly patients with and without dementia and to find out whether a diagnosis of dementia affects the rate of use of drugs or of indwelling urinary catheters (tubes inserted into the bladder to drain urine from the body) for the treatment of urinary incontinence.
What Did the Researchers Do and Find?
The researchers extracted data collected between 2001 and 2010 on incontinence for nearly 55,000 people aged 60–89 with a diagnosis of dementia (the dementia cohort) and for more than 200,000 individuals without a diagnosis of dementia (the non-dementia cohort) from The Health Improvement Network (THIN) primary care database, which includes anonymized consultation records from nearly 500 UK general practices. In the dementia cohort, the rates of first diagnosis of urinary incontinence were 42.3 and 33.5 per 1,000 person-years at risk among men and women, respectively. In the non-dementia cohort, the corresponding rates were 19.8 and 18.6. The rates of first diagnosis of fecal incontinence were 11.1 and 10.1 in the dementia cohort, and 3.1 and 3.6 in the non-dementia cohort among men and women, respectively. After adjusting for age, sex and other diseases, the adjusted rate ratio for the first diagnosis of urinary incontinence in people with dementia compared to people without dementia was 3.2 in men and 2.7 in women; for fecal incontinence, it was 6.0 in men and 4.5 in women; the adjusted rate ratio was 2.2 for both men and women for drug treatment of urinary incontinence and 1.6 in men and 2.3 in women for use of indwelling urinary catheters.
What Do These Findings Mean?
These findings indicate that, in primary care in the UK, dementia is associated with a three-fold higher rate of diagnosis of urinary incontinence and a greater than four-fold higher rate of diagnosis of fecal incontinence. Moreover, the authors suggest that some aspects of clinical management of urinary continence vary between people with and without dementia. In particular, the use of indwelling urinary catheters appears to be more common among people with dementia than among people without dementia, increasing the risk of infection. Thus, health care practitioners providing care for people with dementia may be prioritizing ease of management over risk avoidance, a possibility that requires further investigation. Although the accuracy of these findings is limited by certain aspects of the study design (for example, the THIN database does not identify which patients are living in care homes), they nevertheless suggest that policymakers and insurers involved in planning and providing services for people with dementia living at home need to provide high levels of help with incontinence, including the provision of advice and support for carers.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001505.
The UK not-for-profit organization Alzheimers Society provides information for patients and carers about dementia, including information on coping with incontinence and personal stories about living with dementia
The US not-for-profit organization Alzheimers Association also provides information for patients and carers about dementia and about incontinence, and personal stories about dementia
The UK National Health Service Choices website provides information (including personal stories) about dementia, urinary incontinence, and bowel incontinence
MedlinePlus provides links to further resources about dementia, urinary incontinence and fecal incontinence (in English and Spanish)
The International Continence Society and the International Consultation on Urological Diseases provide independent advice on products to manage incontinence
More information about the THIN database is available
doi:10.1371/journal.pmed.1001505
PMCID: PMC3754889  PMID: 24015113
2.  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
3.  Anterolateral Thigh Flow-Through Flap in Hand Salvage 
Eplasty  2013;13:e19.
Objective: Hand salvage and reconstruction following trauma and oncologic resection often dictates the use of innovative reconstructive techniques. Preservation of functional anatomy is paramount to success in this clinical setting. Further constraints are placed on the reconstructive surgeon in the setting of the aging US population. We report a case of successful hand salvage in an elderly patient using a free anterolateral thigh flow-through flap. Methods: A retrospective chart review was performed on prospectively entered data to examine the case in detail. Indications, radiographs, and follow-up visits were reviewed. A free anterolateral thigh flap was harvested and used to provide soft tissue coverage as well as reconstruction of the palmar arch. Results: The free anterolateral thigh flap not only reconstructed the unique soft tissue envelope of the hand but also restored functional vascular anatomy by reconstituting the interrupted superficial palmar arch. The patient had an uneventful hospital course and was discharged without complications. Conclusions: The free anterolateral thigh flap is a versatile flap that can be used as an innovative solution for hand salvage where vascular anatomy and soft tissue need to be restored.
PMCID: PMC3624776  PMID: 23641298
4.  Genetic Predisposition to Increased Blood Cholesterol and Triglyceride Lipid Levels and Risk of Alzheimer Disease: A Mendelian Randomization Analysis 
PLoS Medicine  2014;11(9):e1001713.
In this study, Proitsi and colleagues use a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset Alzheimer's Disease (LOAD) and find that genetic predisposition to increased plasma cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk.
Please see later in the article for the Editors' Summary
Background
Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD.
Methods and Findings
We included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n = 10,578). We constructed weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at p<5×10−8 and trait specific scores using SNPs associated exclusively with each trait at p<5×10−8 were developed. We used logistic regression to investigate whether the GRSs were associated with LOAD in each study and results were combined together by meta-analysis. We found no association between any of the full GRSs and LOAD (meta-analysis results: odds ratio [OR] = 1.005, 95% CI 0.82–1.24, p = 0.962 per 1 unit increase in HDL-c; OR = 0.901, 95% CI 0.65–1.25, p = 0.530 per 1 unit increase in LDL-c; OR = 1.104, 95% CI 0.89–1.37, p = 0.362 per 1 unit increase in triglycerides; and OR = 0.954, 95% CI 0.76–1.21, p = 0.688 per 1 unit increase in total cholesterol). Results for the trait specific scores were similar; however, the trait specific scores explained much smaller phenotypic variance.
Conclusions
Genetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. The observed epidemiological associations between abnormal lipid levels and LOAD risk could therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD. Limitations of this study include the small proportion of lipid variance explained by the GRS, biases in case-control ascertainment, and the limitations implicit to Mendelian randomization studies. Future studies should focus on larger LOAD datasets with longitudinal sampled peripheral lipid measures and other markers of lipid metabolism, which have been shown to be altered in LOAD.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 44 million people worldwide have dementia, a group of brain disorders characterized by an irreversible decline in memory, communication, and other “cognitive” functions. Dementia mainly affects older people and, because people are living longer, experts estimate that more than 135 million people will have dementia by 2050. The commonest form of dementia is Alzheimer disease. In this type of dementia, protein clumps called plaques and neurofibrillary tangles form in the brain and cause its degeneration. The earliest sign of Alzheimer disease is usually increasing forgetfulness. As the disease progresses, affected individuals gradually lose their ability to deal with normal daily activities such as dressing. They may become anxious or aggressive or begin to wander. They may also eventually lose control of their bladder and of other physical functions. At present, there is no cure for Alzheimer disease although some of its symptoms can be managed with drugs. Most people with the disease are initially cared for at home by relatives and other unpaid carers, but many patients end their days in a care home or specialist nursing home.
Why Was This Study Done?
Several lines of evidence suggest that lipid metabolism (how the body handles cholesterol and other fats) is altered in patients whose Alzheimer disease develops after the age of 60 years (late onset Alzheimer disease, LOAD). In particular, epidemiological studies (observational investigations that examine the patterns and causes of disease in populations) have found an association between high amounts of cholesterol in the blood in midlife and the risk of LOAD. However, observational studies cannot prove that abnormal lipid metabolism (dyslipidemia) causes LOAD. People with dyslipidemia may share other characteristics that cause both dyslipidemia and LOAD (confounding) or LOAD might actually cause dyslipidemia (reverse causation). Here, the researchers use “Mendelian randomization” to examine whether lifetime changes in lipid metabolism caused by genes have a causal impact on LOAD risk. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the effect of a modifiable risk factor and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if dyslipidemia causes LOAD, genetic variants that affect lipid metabolism should be associated with an altered risk of LOAD.
What Did the Researchers Do and Find?
The researchers investigated whether genetic predisposition to raised lipid levels increased the risk of LOAD in 10,578 participants (3,914 patients with LOAD, 1,675 elderly people without LOAD, and 4,989 population controls) using data collected in six genome wide studies looking for gene variants associated with Alzheimer disease. The researchers constructed a genotype risk score (GRS) for each participant using genetic risk markers for four types of blood lipids on the basis of the presence of single nucleotide polymorphisms (SNPs, a type of gene variant) in their DNA. When the researchers used statistical methods to investigate the association between the GRS and LOAD among all the study participants, they found no association between the GRS and LOAD.
What Do These Findings Mean?
These findings suggest that the genetic predisposition to raised blood levels of four types of lipid is not causally associated with LOAD risk. The accuracy of this finding may be affected by several limitations of this study, including the small proportion of lipid variance explained by the GRS and the validity of several assumptions that underlie all Mendelian randomization studies. Moreover, because all the participants in this study were white, these findings may not apply to people of other ethnic backgrounds. Given their findings, the researchers suggest that the observed epidemiological associations between abnormal lipid levels in the blood and variation in lipid levels for reasons other than genetics, or to LOAD risk could be secondary to variation in lipid levels for reasons other than genetics, or to LOAD, a possibility that can be investigated by studying blood lipid levels and other markers of lipid metabolism over time in large groups of patients with LOAD. Importantly, however, these findings provide new information about the role of lipids in LOAD development that may eventually lead to new therapeutic and public-health interventions for Alzheimer disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001713.
The UK National Health Service Choices website provides information (including personal stories) about Alzheimer's disease
The UK not-for-profit organization Alzheimer's Society provides information for patients and carers about dementia, including personal experiences of living with Alzheimer's disease
The US not-for-profit organization Alzheimer's Association also provides information for patients and carers about dementia and personal stories about dementia
Alzheimer's Disease International is the international federation of Alzheimer disease associations around the world; it provides links to individual associations, information about dementia, and links to World Alzheimer Reports
MedlinePlus provides links to additional resources about Alzheimer's disease (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001713
PMCID: PMC4165594  PMID: 25226301
5.  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
6.  Dementia in Down’s syndrome: an MRI comparison with Alzheimer’s disease in the general population 
Background
Down’s syndrome (DS) is the most common genetic cause of intellectual disability. People with DS are at an increased risk of Alzheimer’s disease (AD) compared to the general population. Neuroimaging studies of AD have focused on medial temporal structures; however, to our knowledge, no in vivo case–control study exists comparing the anatomy of dementia in DS to people with AD in the general population. We therefore compared the in vivo brain anatomy of people with DS and dementia (DS+) to those with AD in the general population.
Method
Using MRI in 192 adults, we compared the volume of whole brain matter, lateral ventricles, temporal lobes and hippocampus in DS subjects with and without dementia (DS+, DS-), to each other and to three non-DS groups. These included one group of individuals with AD and two groups of controls (each age-matched for their respective DS and general population AD cohorts).
Results
AD and DS+ subjects showed significant reductions in the volume of the whole brain, hippocampus and temporal lobes and a significant elevation in the volume of the lateral ventricle, compared to their non-demented counterparts. People with DS+ had a smaller reduction in temporal lobe volume compared to individuals with AD.
Conclusions
DS+ and AD subjects have a significant reduction in volume of the same brain regions. We found preliminary evidence that DS individuals may be more sensitive to tissue loss than others and have less ‘cognitive reserve’.
doi:10.1186/1866-1955-5-19
PMCID: PMC3765707  PMID: 23962297
Dementia; Imaging; Intellectual disability
7.  No Change in Physician Dictation Patterns When Visit Notes Are Made Available Online for Patients 
Mayo Clinic Proceedings  2011;86(5):397-405.
OBJECTIVE: To determine whether physicians document office visits differently when they know their patients have easy, online access to visit notes.
PATIENTS AND METHODS: We conducted a natural experiment with a pre-post design and a nonrandomized control group. The setting was a multispecialty group practice in Minnesota. We reviewed a total of 400 visit notes: 100 each for patients seen in a rheumatology department (intervention group) and a pulmonary medicine department (control group) from July 1 to August 30, 2005, before online access to notes, and 100 each for patients seen in these 2 departments 1 year later, from July 1 to August 30, 2006, when only rheumatology patients had online access to visit notes. We measured changes in visit note content related to 9 hypotheses for increased patient understanding and 5 for decreased frank or judgmental language.
RESULTS: Changes occurred for 2 of the 9 hypotheses related to patient understanding, both in an unpredicted direction. The proportion of acronyms or abbreviations increased more in the notes of rheumatologists than of pulmonologists (0.6% vs 0.1%; P=.01), whereas the proportion of anatomy understood decreased more in the notes of rheumatologists than of pulmonologists (−5.9% vs −0.8%; P=.02). One change (of 5 possible) occurred related to the use of frank or judgmental terms. Mentions of mental health status decreased in rheumatology notes and increased in pulmonology notes (−8% vs 7%; P=.02).
CONCLUSION: Dictation patterns appear relatively stable over time with or without online patient access to visit notes.
Physicians have expressed concern that sharing visit notes with patients could lead them to write more vague notes so as to avoid upsetting patients, but this study found that dictation patterns appear relatively stable over time with or without online patient access to visit notes.
doi:10.4065/mcp.2010.0785
PMCID: PMC3084642  PMID: 21531883
8.  Cognitive and Anatomic Contributions of Metabolic Decline in Alzheimer Disease and Cerebrovascular Disease 
Archives of neurology  2008;65(5):650-655.
Background:
Alzheimer disease and cerebrovascular disease affect elderly persons through alterations in brain structure and metabolism that produce cognitive decline. Understanding how each disease contributes to dementia is essential from both a pathophysiologic and diagnostic perspective.
Objective:
To elucidate how baseline cognitive function (episodic memory and executive function) and brain anatomy (white matter hyperintensities and hippocampal volume) are associated with baseline (positron emission tomography-1 [PET1]) and longitudinal (PET2) glucose metabolism in 38 subjects older than 55 years ranging from normal cognition, cognitive impairment without dementia, and dementia.
Design:
Cross-sectional regression analyses across subjects.
Setting:
Multicenter, university-based study of subcortical vascular dementia.
Main Outcome Measures:
Regional cerebral glucose metabolism was the primary outcome, with the major hypotheses that memory and hippocampal volume are related to temporoparietal hypometabolism while executive function and white matter hyperintensities correlate with frontal lobe hypometabolism.
Results:
Low baseline hippocampal volume predicted longitudinal development (PET2) of medial temporal hypometabolism. Lower memory was associated with parietal and cingulate hypometabolism at PET1, which increased at the 2-year-follow-up (PET2). Executive function was associated with frontal and temporoparietal hypometabolism at PET1 but only with frontal hypometabolism at follow-up. White matter hyperintensities predicted hypometabolism over time in the frontoparietal regions, predicting a rate of metabolic change (PET1−PET2/time).
Conclusions:
Low baseline episodic memory and hippocampal volume predict the metabolic alterations associated with Alzheimer disease, whereas elevated baseline white matter hyperintensities predict a different pattern of metabolic decline that is plausibly associated with cerebrovascular disease.
doi:10.1001/archneur.65.5.650
PMCID: PMC2556212  PMID: 18474742
9.  Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations 
Brain  2012;135(3):693-708.
The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as the cause of chromosome 9-linked frontotemporal dementia and motor neuron disease offers the opportunity for greater understanding of the relationship between these disorders and other clinical forms of frontotemporal lobar degeneration. In this study, we screened a cohort of 398 patients with frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 mutations, representing 8% of the cohort. The patients’ clinical phenotype at presentation varied: nine patients had frontotemporal dementia with motor neuron disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia with frontal features and three had progressive non-fluent aphasia. There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease. Nevertheless, 46 patients, including 22 familial, had motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the patients with C9ORF72 mutations presented with psychosis, with a further 28% exhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation bearers presented similarly. The presence of psychosis dramatically increased the odds that patients carried the mutation. Mutation bearers showed a low incidence of motor stereotypies, and relatively high incidence of complex repetitive behaviours, largely linked to patients’ delusions. They also showed a lower incidence of acquired sweet food preference than patients without C9ORF72 mutations. Post-mortem pathology in five patients revealed transactive response DNA-binding protein 43 pathology, type A in one patient and type B in three. However, one patient had corticobasal degeneration pathology. The findings indicate that C9ORF72 mutations cause some but not all cases of frontotemporal dementia with motor neuron disease. Other mutations remain to be discovered. C9ORF72 mutations are associated with variable clinical presentations and pathology. Nevertheless, the findings highlight a powerful association between C9ORF72 mutations and psychosis and suggest that the behavioural characteristics of patients with C9ORF72 mutations are qualitatively distinct. Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis.
doi:10.1093/brain/awr355
PMCID: PMC3286329  PMID: 22300873
frontotemporal lobar degeneration; clinical characteristics; motor neuron disease; psychosis; neuropathology
10.  Another VCP interactor: NF is enough 
The Journal of Clinical Investigation  2011;121(12):4627-4630.
Inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) is a multisystem degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. How missense mutations in this abundant, ubiquitously expressed, multifunctional protein lead to the degeneration of disparate tissues is unclear. VCP participates in diverse cellular functions by associating with an expanding collection of substrates and cofactors that dictate its functionality. In this issue of the JCI, Wang and colleagues have further expanded the VCP interactome by identifying neurofibromin-1 (NF1) as a novel VCP interactor in the CNS. IBMPFD-associated mutations disrupt binding of VCP to NF1, resulting in reduced synaptogenesis. Thus, aberrant interactions between VCP and NF1 may explain the dementia phenotype and cognitive delay observed in patients with IBMPFD and neurofibromatosis type 1.
doi:10.1172/JCI61126
PMCID: PMC3226341  PMID: 22105166
11.  Different Patterns of Cerebral Injury in Dementia with or Without Diabetes 
Archives of neurology  2009;66(3):315-322.
Background
Diabetes mellitus (DM) increases the risk of dementia in the elderly. However the underlying mechanisms, its connection with Alzheimer's disease (AD) and vascular cognitive impairment (VCI), and effects of therapy remain unclear.
Objective
To test the hypothesis that DM promotes specific neuropathologic processes that contribute to dementia and that these processes may be suppressed by antidiabetic therapy.
Design
A comprehensive neuropathologic assessment of all cases from a community-based study of incident dementia (Adult Changes in Thought study) that underwent autopsies (n=259) and had information on DM status (n=196). Biochemical analysis was conducted on a subset of these cases with rapidly frozen brain tissue (n=57).
Participants
Autopsy cases were divided into four groups: no DM/no dementia (DM−/dementia−), DM/no dementia (DM+/dementia−), no DM/dementia (DM−/dementia+), and DM/dementia (DM+/ dementia+). Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnosis of dementia was assigned through a consensus of experts following biennial cognitive and physical evaluations. Diabetes was diagnosed based on information obtained from participants’ extensive medical records.
Results
In cases without dementia (n=125), neuropathologic or biochemical endpoints did not differ significantly by DM status. However, we observed 2 patterns of injury in patients with dementia (n=71) by their DM status. Individuals without DM, but with dementia (DM−/dementia+) had greater Aβ peptide load and increased F2-isoprostanes in the cerebral cortex, while DM+/dementia+ patients had more microvascular infarcts (MVI) and an increased cortical IL-6 (interleukin 6) concentration. The number of microvascular infarcts was greater in deep cerebral structures in patients with dementia whose diabetes was treated, whereas amyloid plaque load tended to be greater for untreated diabetic patients with dementia.
Conclusions
These novel characterizations of 2 different patterns of cerebral injury in patients with dementia depending on DM status may have etiologic and therapeutic implications.
doi:10.1001/archneurol.2008.579
PMCID: PMC2766529  PMID: 19139294
12.  ALS motor phenotype heterogeneity, focality, and spread 
Neurology  2009;73(10):805-811.
Heterogeneity of motor phenotypes is a clinically well-recognized fundamental aspect of amyotrophic lateral sclerosis (ALS) and is determined by variability of 3 independent primary attributes: body region of onset; relative mix of upper motor neuron (UMN) and lower motor neuron (LMN) deficits; and rate of progression. Motor phenotypes are determined by the anatomy of the underlying neuropathology and the common defining elements underlying their heterogeneity are that motor neuron degeneration is fundamentally a focal process and that it spreads contiguously through the 3-dimensional anatomy of the UMN and LMN levels, thus causing seemingly complex and varied clinical manifestations. This suggests motor neuron degeneration in ALS is in actuality a very orderly and actively propagating process and that fundamental molecular mechanisms may be uniform and their chief properties deduced. This also suggests opportunities for translational research to seek pathobiology directly in the less affected regions of the nervous system.
GLOSSARY
= amyotrophic lateral sclerosis;
= frontotemporal dementia;
= lower motor neuron;
= upper motor neuron.
doi:10.1212/WNL.0b013e3181b6bbbd
PMCID: PMC2739608  PMID: 19738176
13.  Utilizing Descriptive Statements from the Biodiversity Heritage Library to Expand the Hymenoptera Anatomy Ontology 
PLoS ONE  2013;8(2):e55674.
Hymenoptera, the insect order that includes sawflies, bees, wasps, and ants, exhibits an incredible diversity of phenotypes, with over 145,000 species described in a corpus of textual knowledge since Carolus Linnaeus. In the absence of specialized training, often spanning decades, however, these articles can be challenging to decipher. Much of the vocabulary is domain-specific (e.g., Hymenoptera biology), historically without a comprehensive glossary, and contains much homonymous and synonymous terminology. The Hymenoptera Anatomy Ontology was developed to surmount this challenge and to aid future communication related to hymenopteran anatomy, as well as provide support for domain experts so they may actively benefit from the anatomy ontology development. As part of HAO development, an active learning, dictionary-based, natural language recognition tool was implemented to facilitate Hymenoptera anatomy term discovery in literature. We present this tool, referred to as the ‘Proofer’, as part of an iterative approach to growing phenotype-relevant ontologies, regardless of domain. The process of ontology development results in a critical mass of terms that is applied as a filter to the source collection of articles in order to reveal term occurrence and biases in natural language species descriptions. Our results indicate that taxonomists use domain-specific terminology that follows taxonomic specialization, particularly at superfamily and family level groupings and that the developed Proofer tool is effective for term discovery, facilitating ontology construction.
doi:10.1371/journal.pone.0055674
PMCID: PMC3575469  PMID: 23441153
14.  Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 
Brain  2012;135(3):765-783.
Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.
doi:10.1093/brain/aws004
PMCID: PMC3286335  PMID: 22366793
frontotemporal dementia; amyotrophic lateral sclerosis; motor neuron disease; TDP-43; neurogenetics; chromosome 9
15.  Severity of CIND and MCI predict incidence of dementia in an ischemic stroke cohort 
Neurology  2009;73(22):1866-1872.
Background:
The utility of poststroke cognitive status, namely dementia, cognitive impairment no dementia (CIND), mild cognitive impairment (MCI), and no cognitive impairment (NCI), in predicting dementia has been previously examined. However, no studies to date have compared the ability of subtypes of MCI and CIND to predict dementia in a poststroke population.
Methods:
A cohort of ischemic stroke patients underwent neuropsychological assessment annually for up to 5 years. Dementia was defined using the DSM-IV criteria. Univariate and multivariable Cox proportional regression was performed to determine the ability of MCI subtypes, CIND severity, and individual domains of impairment to predict dementia.
Results:
A total of 362 patients without dementia were followed up for a mean of 3.4 years (17% drop out), with 24 developing incident dementia. Older age, previous and recurrent stroke, and CIND and MCI subtypes were significant predictors of dementia. In multivariable analysis controlling for treatment allocation, patients who were older, had previous or recurrent stroke, and had either CIND moderate or multiple domain MCI with amnestic component were at elevated risk for dementia. In multivariable domain analysis, recurrent strokes, age, and previous strokes, verbal memory, and visual memory were significant predictors of dementia. Receiver operating characteristic curve analysis showed that CIND moderate (area under the curve: 0.893) and multiple domain MCI with amnestic component (area under the curve: 0.832) were significant predictors of conversion to dementia. All other classifications of cognitive impairment had areas under the curve less than 0.7.
Conclusion:
Stroke patients with cognitive impairment no dementia (CIND) moderate are at higher risk of developing dementia, while CIND mild patients are not at increased risk of developing dementia.
GLOSSARY
= Alzheimer disease;
= area under the curve;
= confidence interval;
= cognitive impairment no dementia;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= European Australasian Stroke Prevention in Reversible Ischemia Trial;
= European Australasian Stroke Prevention in Reversible Ischemia Trial, cognitive substudy;
= hazard ratio;
= lacunar infarct;
= mild cognitive impairment;
= modified Rankin scale;
= no cognitive impairment;
= Oxfordshire Community Stroke Project;
= partial anterior circulation infarct;
= posterior circulation infarct;
= receiver operating curve;
= total anterior circulation infarct;
= vascular dementia;
= Wechsler Adult Intelligence Scale–Revised;
= Wechsler Memory Scale–Revised.
doi:10.1212/WNL.0b013e3181c3fcb7
PMCID: PMC2788800  PMID: 19949033
16.  Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study 
Brain  2012;135(9):2809-2816.
Recent studies suggest that delirium is associated with risk of dementia and also acceleration of decline in existing dementia. However, previous studies may have been confounded by incomplete ascertainment of cognitive status at baseline. Herein, we used a true population sample to determine if delirium is a risk factor for incident dementia and cognitive decline. We also examined the effect of delirium at the pathological level by determining associations between dementia and neuropathological markers of dementia in patients with and without a history of delirium. The Vantaa 85+ study examined 553 individuals (92% of those eligible) aged ≥85 years at baseline, 3, 5, 8 and 10 years. Brain autopsy was performed in 52%. Fixed and random-effects regression models were used to assess associations between (i) delirium and incident dementia and (ii) decline in Mini-Mental State Examination scores in the whole group. The relationship between dementia and common neuropathological markers (Alzheimer-type, infarcts and Lewy-body) was modelled, stratified by history of delirium. Delirium increased the risk of incident dementia (odds ratio 8.7, 95% confidence interval 2.1–35). Delirium was also associated with worsening dementia severity (odds ratio 3.1, 95% confidence interval 1.5–6.3) as well as deterioration in global function score (odds ratio 2.8, 95% confidence interval 1.4–5.5). In the whole study population, delirium was associated with loss of 1.0 more Mini-Mental State Examination points per year (95% confidence interval 0.11–1.89) than those with no history of delirium. In individuals with dementia and no history of delirium (n = 232), all pathologies were significantly associated with dementia. However, in individuals with delirium and dementia (n = 58), no relationship between dementia and these markers was found. For example, higher Braak stage was associated with dementia when no history of delirium (odds ratio 2.0, 95% confidence interval 1.1–3.5, P = 0.02), but in those with a history of delirium, there was no significant relationship (odds ratio 1.2, 95% confidence interval 0.2–6.7, P = 0.85). This trend for odds ratios to be closer to unity in the delirium and dementia group was observed for neuritic amyloid, apolipoprotein ε status, presence of infarcts, α-synucleinopathy and neuronal loss in substantia nigra. These findings are the first to demonstrate in a true population study that delirium is a strong risk factor for incident dementia and cognitive decline in the oldest-old. However, in this study, the relationship did not appear to be mediated by classical neuropathologies associated with dementia.
doi:10.1093/brain/aws190
PMCID: PMC3437024  PMID: 22879644
delirium; dementia; neuropathology; population-based; epidemiology
17.  A population study of apoE genotype at the age of 85: relation to dementia, cerebrovascular disease, and mortality 
OBJECTIVES—To study the association of apoE genotypes with dementia and cerebrovascular disorders in a population based sample of 85year old people.
METHODS—A representative sample of 85 year old people (303 non-demented, 109 demented) were given a neuropsychiatric and a medical examination and head CT. The apoE isoforms were determined. Dementia was diagnosed according to DSM-III-R.
RESULTS—At the age of 85, carriers of the apoE ε4 allele had an increased odds ratio (OR) for dementia (1.9; p<0.01) and its subtypes Alzheimer's disease (1.9; p<0.05) and vascular dementia (2.0; p<0.05). Among those categorised as having vascular dementia, the apoE ε4 allele was associated with mixed Alzheimer's disease-multi-infarct dementia (OR 6.5; p<0.05), but not with pure multi-infarct dementia (OR 1.5; NS). Only carriers of the apoE ε4 allele who also had ischaemic white matter lesions on CT of the head had an increased OR for dementia (OR 6.1; p=0.00003), and its main subtypes Alzheimer's disease (OR 6.8; p=0.002) and vascular dementia (OR 5.6; p=0.0007), whereas carriers of the apoE ε4 allele without white matter lesions had an OR for dementia of 1.0 (OR for Alzheimer's disease 1.8; NS and for vascular dementia 0.6; NS) and non-carriers of the apoE ε4 allele with white matter lesions had an OR for dementia of 2.2; NS (OR for Alzheimer's disease 2.7; NS and for vascular dementia 1.6; NS). The apoE allele variants were not related to mortality or incidence of dementia between the ages of 85 and 88. The ε2 allele was related to a higher prevalence of stroke or transient ischaemic attack at the age of 85 (OR 2.1; p<0.05) and a higher incidence of multi-infarct dementia during the follow up (OR 2.9; p<0.05).
CONCLUSIONS—Neither the apoE ε4 allele nor white matter lesions are sufficient risk factors by themselves for dementia at very old ages, whereas possession of both these entities increases the risk for Alzheimer's disease and vascular dementia substantially.


PMCID: PMC2169928  PMID: 9436725
18.  A Case of Generalized Auditory Agnosia with Unilateral Subcortical Brain Lesion 
Annals of Rehabilitation Medicine  2012;36(6):866-870.
The mechanisms and functional anatomy underlying the early stages of speech perception are still not well understood. Auditory agnosia is a deficit of auditory object processing defined as a disability to recognize spoken languages and/or nonverbal environmental sounds and music despite adequate hearing while spontaneous speech, reading and writing are preserved. Usually, either the bilateral or unilateral temporal lobe, especially the transverse gyral lesions, are responsible for auditory agnosia. Subcortical lesions without cortical damage rarely causes auditory agnosia. We present a 73-year-old right-handed male with generalized auditory agnosia caused by a unilateral subcortical lesion. He was not able to repeat or dictate but to perform fluent and comprehensible speech. He could understand and read written words and phrases. His auditory brainstem evoked potential and audiometry were intact. This case suggested that the subcortical lesion involving unilateral acoustic radiation could cause generalized auditory agnosia.
doi:10.5535/arm.2012.36.6.866
PMCID: PMC3546192  PMID: 23342322
Auditory agnosia; Unilateral subcortical lesion
19.  Using Exome Sequencing to Reveal Mutations in TREM2 Presenting as a Frontotemporal Dementia–like Syndrome Without Bone Involvement 
JAMA neurology  2013;70(1):78-84.
Objective
To identify new genes and risk factors associated with frontotemporal dementia (FTD). Several genes and loci have been associated with different forms of FTD, but a large number of families with dementia do not harbor mutations in these genes.
Design
Whole-exome sequencing and whole-genome genotyping were performed in all patients. Genetic variants obtained from whole-exome sequencing were integrated with the data obtained from whole-genome genotyping.
Setting
Database of the Behavioral Neurology Outpatient Clinic of the Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey.
Patients
Forty-four Turkish patients with an FTD-like clinical diagnosis were included in the study. Relatives were screened when appropriate.
Main Outcome Measure
Mutations in the triggering receptor expressed on myeloid cells 2 gene (TREM2).
Results
In 3 probands with FTD-like disease, we identified different homozygous mutations in TREM2 that had previously been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). None of these 3 patients had a typical clinical presentation of PLOSL: they presented with behavioral change and subsequent cognitive impairment and motor features but without any bone cysts or bone-associated phenotypes. Imaging showed white matter abnormalities as well as frontal atrophy in all 3 patients.
Conclusions
Our results show that TREM2 is responsible for an unexpectedly high number of dementia cases in our cohort, suggesting that this gene should be taken into account when mutations in other dementia genes are excluded. Even for complex syndromes such as dementia, exome sequencing has proven to be a rapid and cost-effective tool to identify genetic mutations, allowing for the association of clinical phenotypes with unexpected molecular underpinnings.
doi:10.1001/jamaneurol.2013.579
PMCID: PMC4001789  PMID: 23318515
20.  Diagnosis and treatment of dementia: 5. Nonpharmacologic and pharmacologic therapy for mild to moderate dementia 
Background
Practising physicians frequently seek advice on the most effective interventions for dementia. In this article, we provide practical guidance on nonpharmacologic and pharmacologic interventions for the management of mild to moderate dementia based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia.
Methods
We developed evidence-based guidelines using systematic literature searches, with specific criteria for the selection and quality assessment of articles, and a clear and transparent decision-making process. We selected articles published from January 1996 to December 2005 that dealt with the management of mild to moderate stages of Alzheimer disease and other forms of dementia. Recommendations based on the literature review were drafted and voted on. Consensus required 80% or more agreement by participants. Subsequent to the conference, we searched for additional articles published from January 2006 to April 2008 using the same major keywords and secondary search terms. We graded the strength of the evidence using the criteria of the Canadian Task Force on Preventive Health Care.
Results
We identified 1615 articles, of which 954 were selected for further study. From a synthesis of the evidence in these studies, we made 48 recommendations for the management of mild to moderate dementia (28) and dementia with a cerebrovascular component (8) as well as recommendations for addressing ethical issues (e.g., disclosure of the diagnosis) (12). The updated literature review did not change these recommendations. An exercise program is recommended for patients with mild to moderate dementia. Physicians should decide whether to prescribe a cholinesterase inhibitor on an individual basis, balancing anticipated benefits with the potential for harm. For mild mood and behavioural concerns, nonpharmacologic approaches should be considered first.
Interpretation
Although the available therapies for dementia can help with the management of symptoms, there is a need to develop more effective interventions.
Articles to date in this seriesChertkow H. Diagnosis and treatment of dementia: Introduction. Introducing a series based on the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. CMAJ 2008;178:316-21.Patterson C, Feightner JW, Garcia A, et al. Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease. CMAJ 2008;178:548-56.Feldman HH, Jacova C, Robillard A, et al. Diagnosis and treatment of dementia: 2. Diagnosis. CMAJ 2008;178:825-36.Chertkow H, Massoud F, Nasreddine Z, et al. Diagnosis and treatment of dementia: 3. Mild cognitive impairment and cognitive impairment without dementia. CMAJ 2008;178:1273-85.Hogan DB, Bailey P, Black S, et al. Diagnosis and treatment of dementia: 4. Approach to management of mild to moderate dementia. CMAJ 2008;179:787-93.
doi:10.1503/cmaj.081103
PMCID: PMC2572644  PMID: 18981443
21.  FATTY DEGENERATION OF THE CEREBRAL CORTEX IN THE PSYCHOSES, WITH SPECIAL REFERENCE TO DEMENTIA PRÆCOX 
From the data provided by our investigations we may conclude that in all pathologic processes of the cortex which end in dementia and death, the fatty degeneration of the elements of the cortex plays a not unimportant part. The characteristic change for most of the psychoses is found in a great increase in amount of fatty deposits when compared to normal individuals of the same age. In some processes such as senile dementia and dementia præcox the fatty substance appears to fill completely the cell body, and these cells have apparently lost all their functioning power. It is not common to find the fatty deposits in the processes of the ganglion cells except in dementia præcox, and to a limited extent in senile dementia. In other cases the pathological variety of the fatty deposits in the ganglion cells is seen to be diffused over the whole ganglion cell. We were able especially to observe this in infectious psychoses, in general paralysis, and in epilepsy. The so called central neuritis assumes a peculiar attitude in that it plainly leads swiftly to an acute fatty degeneration of the ganglion cells, in which there exists an inclination of the fatty granules to flow together into large masses. Frequently the fatty degeneration of the ganglion cells appears to be connected with the sclerosis of the cells, especially when it is a matter of slowly progressing alterations of degeneration. The behavior of the glia is not wholly uniform in the various disease processes. In chronic disease processes we often find that the extent of the fatty accumulations in the ganglion cells does not correspond to an equal increase in the glia cells, while the otherwise acutely degenerative alteration in the nuclei of the glia is noticeable. In acute processes we see regularly an equal accumulation of the fat in both species of cell. The conditions of the cells in the vascular wall are wholly similar to those of the glia cells. We must therefore assume that in chronic diseases the fatty substance has been carried out of the glia and the vascular walls while it has been retained longer in the ganglion cells. Among all the disease processes amaurotic idiocy assumes a peculiar position. We have observed that in addition to the fatty materials of the scarlet fat stain, still other fatty materials, lipoid in character, have made their appearance. While the study of the fatty deposit in the cerebral cortex offers some points for a differential diagnosis, yet it is not adopted in all cases, since the distinction in individual disease processes is not always characteristic. From the preceding examination, however, in many cases there result important findings which briefly we summarize as follows: 1. In all degenerative alterations in the cerebral cortex the mass of the lipoid materials in the ganglion cells in comparison with that in healthy individuals of equal age is found to be considerably augmented. In the alteration of the lipoid materials in the ganglion cells two types in general may be distinguished: (a) An augmentation of the lipoid materials in the ganglion cells, in places where normally a small amount of fat is found, (b) An augmentation of the lipoid materials over the entire cell. 2. The first type we find also characteristic in senile dementia. The second type occurs in acute infectious psychoses, general paralysis, and well advanced epilepsy. 3. While the advanced lipoid degeneration of the ganglion cells in senile dementia has already been described in many ways, it has appeared from our investigations that also in the young chronic cases of dementia præcox far-reaching fatty degeneration of the ganglion cells, especially in the second and third cortical strata, likewise occurs. These findings should constitute an important contribution to the pathological anatomy of dementia præcox. 4. The so called central neuritis represents a peculiar disease process according to the appearance of the fatty degeneration, since this fatty degeneration reaches a very advanced degree, and also in so far as it deviates from other disease processes in that here there comes out very distinctly in the picture an inclination of the fatty granules to flow together. 5. Amaurotic idiocy also represents a particular disease process in respect to the lipoid degeneration, since here in addition to otherwise distributed scarlet stain lipoid materials, still other specific lipoid materials make their appearance.
PMCID: PMC2125354  PMID: 19867933
22.  Motor Phenotype of Decline in Cognitive Performance among Community-Dwellers without Dementia: Population-Based Study and Meta-Analysis 
PLoS ONE  2014;9(6):e99318.
Background
Decline in cognitive performance is associated with gait deterioration. Our objectives were: 1) to determine, from an original study in older community-dwellers without diagnosis of dementia, which gait parameters, among slower gait speed, higher stride time variability (STV) and Timed Up & Go test (TUG) delta time, were most strongly associated with lower performance in two cognitive domains (i.e., episodic memory and executive function); and 2) to quantitatively synthesize, with a systematic review and meta-analysis, the association between gait performance and cognitive decline (i.e., mild cognitive impairment (MCI) and dementia).
Methods
Based on a cross-sectional design, 934 older community-dwellers without dementia (mean±standard deviation, 70.3±4.9years; 52.1% female) were recruited. A score at 5 on the Short Mini-Mental State Examination defined low episodic memory performance. Low executive performance was defined by clock-drawing test errors. STV and gait speed were measured using GAITRite system. TUG delta time was calculated as the difference between the times needed to perform and to imagine the TUG. Then, a systematic Medline search was conducted in November 2013 using the Medical Subject Heading terms “Delirium,” “Dementia,” “Amnestic,” “Cognitive disorders” combined with “Gait” OR “Gait disorders, Neurologic” and “Variability.”
Findings
A total of 294 (31.5%) participants presented decline in cognitive performance. Higher STV, higher TUG delta time, and slower gait speed were associated with decline in episodic memory and executive performances (all P-values <0.001). The highest magnitude of association was found for higher STV (effect size  =  −0.74 [95% Confidence Interval (CI): −1.05;−0.43], among participants combining of decline in episodic memory and in executive performances). Meta-analysis underscored that higher STV represented a gait biomarker in patients with MCI (effect size  =  0.48 [95% CI: 0.30;0.65]) and dementia (effect size  = 1.06 [95% CI: 0.40;1.72]).
Conclusion
Higher STV appears to be a motor phenotype of cognitive decline.
doi:10.1371/journal.pone.0099318
PMCID: PMC4049832  PMID: 24911155
23.  The Influence of Multimorbidity on Clinical Progression of Dementia in a Population-Based Cohort 
PLoS ONE  2013;8(12):e84014.
Introduction
Co-occurrence with other chronic diseases may influence the progression of dementia, especially in case of multiple chronic diseases. We aimed to verify whether multimorbidity influenced cognitive and daily functioning during nine years after dementia diagnosis compared with the influence in persons without dementia.
Methods
In the Kungsholmen Project, a population-based cohort study, we followed 310 persons with incident dementia longitudinally. We compared their trajectories with those of 679 persons without dementia. Progression was studied for cognition and activities of daily life (ADLs), measured by MMSE and Katz Index respectively. The effect of multimorbidity and its interaction with dementia status was studied using individual growth models.
Results
The mean (SD) follow-up time was 4.7 (2.3) years. As expected, dementia related to both the decline in cognitive and daily functioning. Irrespective of dementia status, persons with more diseases had significantly worse baseline daily functioning. In dementia patients having more diseases also related to a significantly faster decline in daily functioning. Due to the combination of lower functioning in ADLs at baseline and faster decline, dementia patients with multimorbidity were about one to two years ahead of the decline of dementia patients without any co-morbidity. In persons without dementia, no significant decline in ADLs over time was present, nor was multimorbidity related to the decline rate. Cognitive decline measured with MMSE remained unrelated to the number of diseases present at baseline.
Conclusion
Multimorbidity was related to baseline daily function in both persons with and without dementia, and with accelerated decline in people with dementia but not in non-demented individuals. No relationship of multimorbidity with cognitive functioning was established. These findings imply a strong interconnection between physical and mental health, where the greatest disablement occurs when both somatic and mental disorders are present.
doi:10.1371/journal.pone.0084014
PMCID: PMC3875493  PMID: 24386324
24.  The effect of seniority and education on departmental dictation utilization 
Background
Electronic medical records (EMR) are considered the best solution to improved dissemination of health information for patients. The associated transcription caused a significant cost increase in an academic pediatric center. An educational campaign was implemented to achieve cost-effective transcriptions without compromising the number of EMR transcriptions.
Methods
We analyzed the effect of seniority on transcription times over a 4-month period. We also compared the dictation volume before and 4 months after educational interventions. This study was performed in a pediatric academic center with both inpatient and outpatient transcription utilization analyzed. All clinicians providing pediatric care and utilizing the hospital-based transcription over the study time period were analyzed. Interventions included targeted education about efficiencies in transcription, time-based dictation costs, avoidance of lengthy pauses and unnecessary detail, shortening of total transcriptions, superfluous phrases as well as structured templates. Level of training by postgraduate year of training and seniority within faculty were measured for impact on dictation time and effect of education to improve times.
Results
Learners in year one had an average dictation time of 7.5 ± 2.2 minutes, which decreased with seniority to an average of 4.1 ± 2.2 minutes for senior faculty (0.0007, ANOVA). After educational initiatives were implemented, there was progressive decline in dictation utilization. The total dictation time decreased from 8,750 minutes per month in August 2009 to 4,296 minutes in December of 2009 (p = 0.0045, unpaired t-test).
Conclusion
We identified a substantial need for education in dictation utilization and demonstrated that relatively simple interventions can result in substantial costs savings.
doi:10.1186/2191-1991-1-8
PMCID: PMC3402968  PMID: 22827863
dictation utilization; dictation cost; training; accountability; cost effectiveness
25.  Free and Cued Selective Reminding Identifies Very Mild Dementia in Primary Care 
The Free and Cued Selective Reminding Test (FCSRT) is used widely to identify very mild dementia; three alternative scoring procedures have been proposed based on free recall, total recall, and cue efficiency. We compared the predictive validity of these scoring procedures for the identification of very mild prevalent dementia (CDR=0.5), of incident dementia and for distinguishing AD and nonAD dementias. We tested 244 elderly African American and Caucasian primary care patients at 18 month intervals using a screening neuropsychological battery that included the FCSRT and a comprehensive diagnostic neuropsychological battery. Median follow-up was 2.6 years. Dementia diagnoses were assigned using standard criteria without access to the results of the screening battery. There were 50 prevalent and 28 incident dementia cases. At scores selected to provide specificities of 90%, free recall was more sensitive to incident and prevalent dementia than the other two measures. Patients with impaired free recall were 15 times more likely to have a prevalent dementia and their risk of future dementia was four times higher than patients with intact free recall. Neither race nor education affected prediction though older patients were at increased risk of future dementia. Total recall was more impaired in AD dementia than in nonAD dementias. The results indicate that using the FCSRT, free recall is best measure for detecting prevalent dementia and predicting future dementia. Total recall impairment supports the diagnosis of AD rather than nonAD dementia.
doi:10.1097/WAD.0b013e3181cfc78b
PMCID: PMC2929322  PMID: 20683186

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