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1.  The relationship between cerebral amyloid angiopathy and cortical microinfarcts in brain ageing and Alzheimer’s disease 
Cerebral amyloid angiopathy (CAA) represents the deposition of amyloid β protein (Aβ) in the meningeal and intracerebral vessels. It is often observed as an accompanying lesion of Alzheimer’s disease (AD) or in the brain of elderly individuals even in the absence of dementia. CAA is largely age-dependent. In subjects with severe CAA a higher frequency of vascular lesions has been reported. The goal of our study was to define the frequency and distribution of CAA in a one-year autopsy population (91 cases) from the Department of Internal Medicine, Rehabilitation, and Geriatrics, Geneva.
Materials and methods
Five brain regions were examined, including the hippocampus, and the inferior temporal, frontal, parietal, and occipital cortex, using an antibody against Aβ, and simultaneously assessing the severity of AD-type pathology with Braak stages for neurofibrillary tangles identified with an anti-tau antibody. In parallel, the relationships of CAA with vascular brain lesions were established.
CAA was present in 53.8% of the studied population, even in cases without AD (50.6%). The strongest correlation was seen between CAA and age, followed by the severity of amyloid plaques deposition. Microinfarcts were more frequent in cases with CAA; however, our results did not confirm a correlation between these parameters.
The present data show that CAA plays a role in the development of microvascular lesions in the aging brain, but cannot be considered as the most important factor in this vascular pathology, suggesting that other mechanisms also contributes importantly to the pathogenesis of microvascular changes.
PMCID: PMC3637988  PMID: 23163235
amyloid angiopathy; cortical microinfarcts; Alzheimer’s disease; vascular; neuropathology; immunohistochemistry
2.  Violent Deaths of Iraqi Civilians, 2003–2008: Analysis by Perpetrator, Weapon, Time, and Location 
PLoS Medicine  2011;8(2):e1000415.
Madelyn Hsiao-Rei Hicks and colleagues provide a detailed analysis of Iraqi civilian violent deaths during 2003-2008 of the Iraq war and show that of 92,614 deaths, unknown perpetrators caused 74% of deaths, Coalition forces 12%, and Anti-Coalition forces 11%.
Armed violence is a major public health and humanitarian problem in Iraq. In this descriptive statistical analysis we aimed to describe for the first time Iraqi civilian deaths caused by perpetrators of armed violence during the first 5 years of the Iraq war: over time; by weapon used; by region (governorate); and by victim demographics.
Methods and Findings
We analyzed the Iraq Body Count database of 92,614 Iraqi civilian direct deaths from armed violence occurring from March 20, 2003 through March 19, 2008, of which Unknown perpetrators caused 74% of deaths (n = 68,396), Coalition forces 12% (n = 11,516), and Anti-Coalition forces 11% (n = 9,954). We analyzed the subset of 60,481 civilian deaths from 14,196 short-duration events of lethal violence to link individual civilian deaths to events involving perpetrators and their methods. One-third of civilian violent death was from extrajudicial executions by Unknown perpetrators; quadratic regression shows these deaths progressively and disproportionately increased as deaths from other forms of violence increased across Iraq's governorates. The highest average number of civilians killed per event in which a civilian died were in Unknown perpetrator suicide bombings targeting civilians (19 per lethal event) and Coalition aerial bombings (17 per lethal event). In temporal analysis, numbers of civilian deaths from Coalition air attacks, and woman and child deaths from Coalition forces, peaked during the invasion. We applied a Woman and Child “Dirty War Index” (DWI), measuring the proportion of women and children among civilian deaths of known demographic status, to the 22,066 civilian victims identified as men, women, or children to indicate relatively indiscriminate perpetrator effects. DWI findings suggest the most indiscriminate effects on women and children were from Unknown perpetrators using mortar fire (DWI  = 79) and nonsuicide vehicle bombs (DWI  = 54) and from Coalition air attacks (DWI  = 69). Coalition forces had higher Woman and Child DWIs than Anti-Coalition forces, with no evidence of decrease over 2003–2008, for all weapons combined and for small arms gunfire, specifically.
Most Iraqi civilian violent deaths during 2003–2008 of the Iraq war were inflicted by Unknown perpetrators, primarily through extrajudicial executions that disproportionately increased in regions with greater numbers of violent deaths. Unknown perpetrators using suicide bombs, vehicle bombs, and mortars had highly lethal and indiscriminate effects on the Iraqi civilians they targeted. Deaths caused by Coalition forces of Iraqi civilians, women, and children peaked during the invasion period, with relatively indiscriminate effects from aerial weapons.
Please see later in the article for the Editors' Summary
Editors' Summary
Civilian deaths through armed violence is a public health and humanitarian problem in all wars, despite internationally agreed humanitarian standards regarding the treatment of civilians during wars—so-called laws of war such as the Geneva Conventions. Since the Iraq war began on March 20, 2003, when a multilateral force led by US and UK troops invaded Iraq, more than 100,000 Iraqi civilians (women, children, noncombatants, and police carrying out nonparamilitary duties) have died because of armed violence, according to the Iraq Body Count (IBC), a nongovernmental project that collates media reports of deaths of individual Iraqi civilians and cross-checks these reports with data from hospitals, morgues, nongovernmental organizations, and official figures. Indeed, according to a recent assessment of the global burden of armed violence, in 2006, people living in Iraq had the highest risk of dying violently in conflict. In that year, there were 91 violent deaths per 100,000 people in the country.
Why Was This Study Done?
Detailed analysis of civilian deaths during wars is important because it can improve the understanding of the impact of these deaths on general public health and on vulnerable subgroups in the population. In addition, data collected on the nature and effects of violence can guide the development of preventative policies. For example, an analysis that reveals that air attacks by invading troops cause a high proportion of civilian deaths might encourage policy changes that prohibit air attacks on populated areas. Finally, by linking violent deaths to perpetrators, analyses of civilian deaths can provide an indicator of combatants' compliance with the laws of war, which require the protection of civilians from targeted or indiscriminate harm. Here, IBC researchers provide a descriptive statistical analysis of Iraqi civilian deaths directly caused by perpetrators of armed violence during the first 5 years of the Iraq war.
What Did the Researchers Do and Find?
According to data from the Iraq Body Count, more than 92,000 Iraqi civilians died because of armed violence during this period. Coalition forces (identified by uniforms) caused 12% of these deaths, anti-coalition forces (un-uniformed combatants identified by attacks on coalition targets) caused 11% of the deaths; and unknown perpetrators, who targeted civilians and were indistinguishable from their victims (for example, a suicide bomber in a market), were responsible for three-quarters of civilian deaths. To link individual deaths with perpetrators and their methods, the researchers analyzed the 60,481 civilian deaths caused by short-duration events of lethal violence (events that lasted less than 24 hours and that occurred in a specific location; for example, overnight air strikes). Extrajudicial executions by unknown perpetrators were responsible for one-third of these deaths and disproportionately increased as deaths from other forms of violence increased across Iraq. Unknown perpetrator suicide bombings that targeted civilians and coalition aerial bombings killed most civilians per lethal event (19 and 17 deaths per lethal event on average, respectively). Finally, the researchers calculated the proportion of women and children among civilian deaths. Because men are the main targets of armed violence, this proportion—the “Dirty War Index” (DWI)—indicates the scale of indiscriminate killing in a conflict. The most indiscriminate effects on women and children in Iraq were from unknown perpetrators firing mortars (DWI  = 79) and nonsuicide vehicle bombs (DWI  = 54), and from coalition air attacks (DWI  = 69). Coalition forces had a higher DWI than anti-coalition forces for all weapons combined, with no decrease over the study period.
What Do These Findings Mean?
These findings show that during the first 5 years of the Iraq war, civilian deaths varied over time and location and in terms of victim characteristics and targeting of civilians. Although limited to direct deaths and possibly subject to some media bias, these findings show that most civilian deaths were inflicted by unknown perpetrators, and that unknown perpetrators had particularly lethal and indiscriminate effects on Iraqi civilians. However, they also show that Coalition forces had indiscriminate lethal effects on civilian populations. In part, this may be because Coalition forces had a high risk of killing civilians accidentally because they could not easily recognize anti-coalition combatants fighting without uniforms among civilians. Nevertheless, the relatively indiscriminate effects of Coalition aerial weapons highlight the need to change policies relating to the use of air power in future armed conflicts.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Robert Muggah
The International Committee of the Red Cross provides information about war and International humanitarian law (in several languages)
The Geneva Declaration on Armed Violence and Development Web site provides information on the global burden of armed violence
More details on the Iraq Body Count are available
The Human Security Report Project tracks global and regional trends in organized violence, their causes, and consequences
Every Casualty supports and is a resource for the documentation of individual casualties of armed conflict
PMCID: PMC3039690  PMID: 21358813
3.  Autopsy consent, brain collection, and standardized neuropathologic assessment of ADNI participants: The essential role of the Neuropathology Core 
Our objectives are to facilitate autopsy consent, brain collection, and perform standardized neuropathologic assessments of all Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who come to autopsy at the 58 ADNI sites in the USA and Canada.
Building on the expertise and resources of the existing Alzheimer's Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, MO, a Neuropathology Core (NPC) to serve ADNI was established with one new highly motivated research coordinator. The ADNI-NPC coordinator provides training materials and protocols to assist clinicians at ADNI sites in obtaining voluntary consent for brain autopsy in ADNI participants. Secondly, the ADNI-NPC maintains a central laboratory to provide uniform neuropathologic assessments using the operational criteria for the classification of AD and other pathologies defined by the National Alzheimer Coordinating Center (NACC). Thirdly, the ADNI-NPC maintains a state-of-the-art brain bank of ADNI-derived brain tissue to promote biomarker and multi-disciplinary clinicopathologic studies.
During the initial year of funding of the ADNI Neuropathology Core, there was notable improvement in the autopsy rate to 44.4%. In the most recent year of funding (September 1st, 2008 to August 31st 2009), our autopsy rate improved to 71.5%. Although the overall numbers to date are small, these data demonstrate that the Neuropathology Core has established the administrative organization with the participating sites to harvest brains from ADNI participants who come to autopsy.
Within two years of operation, the Neuropathology Core has: (1) implemented a protocol to solicit permission for brain autopsy in ADNI participants at all 58 sites who die and (2) to send appropriate brain tissue from the decedents to the Neuropathology Core for a standardized, uniform, and state-of-the-art neuropathologic assessment. The benefit to ADNI of the implementation of the NPC is very clear. Prior to the establishment of the NPC in September 2007, there were 6 deaths but no autopsies in ADNI participants. Subsequent to the establishment of the Core there have been 17 deaths of ADNI participants and 10 autopsies. Hence, the autopsy rate has gone from 0% to 59%. The third major accomplishment is the detection of co-existent pathologies with AD in the autopsied cases. It is possible that these co-morbidities may contribute to any variance in ADNI data.
PMCID: PMC2893399  PMID: 20451876
Alzheimer's disease; Alzheimer's Disease Neuroimaging Initiative; autopsy consent; brain bank; neuropathologic diagnostic criteria
4.  Midlife blood pressure, plasma β amyloid and the risk for Alzheimer’s disease: the Honolulu Asia Aging Study 
Hypertension  2012;59(4):780-786.
Beta-amyloid (Aβ), a vasoactive protein, and elevated blood pressure (BP) levels are associated with Alzheimer’s disease (AD) and possibly vascular dementia (VaD). We investigated the joint association of mid-life BP and Aβ peptide levels with the risk for late-life AD and VaD. Subjects were 667 Japanese-American men (including 73 with a brain autopsy), from the prospective Honolulu Heart Program/Honolulu Asia Aging Study (1965 – 2000). Mid-life BP was measured starting in 1971 participants mean age 58 years, Aβ was measured in specimens collected1980/82, and assessment of dementia and autopsy collection started in 1991/93. The outcome measures were prevalent (present in 1991/3) and incident AD (n= 53, including 38 with no contributing cardiovascular disease), and VaD (n=24). Cerebral amyloid angiopathy (CAA), β-amyloid neuritic plaques, and neurofibrillary tangles were evaluated in post-mortem tissue. The risk for AD significantly increased with lower levels of plasma Aβ (Aβ1-40 hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.4 – 3.1; Aβ1-42 HR 1.6, 95% CI 1.1 – 2.3). Evidence of interaction between diastolic BP and plasma Aβ (1-40 pinteraction <0.05; 1-42 pinteraction <0.07) levels, indicated the Aβ-related risk for AD was higher when BP was higher. Low plasma Aβ was associated with the presence of CAA (ptrend<0.05), but not the other neuropathologies. Aβ plasma levels start decreasing at least 15 years before AD is diagnosed, and the association of Aβ to AD is modulated by mid-life diastolic BP. Elevated BP may compromise vascular integrity leading to CAA and impaired Aβ clearance from the brain.
PMCID: PMC3319436  PMID: 22392902
Amyloid; blood pressure; brain; aging; dementia
5.  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.
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%).
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
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
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
PMCID: PMC2765638  PMID: 19901977
6.  The Task before Psychiatry Today Redux: STSPIR* 
Mens Sana Monographs  2014;12(1):35-70.
This paper outlines six important tasks for psychiatry today, which can be put in short as:
Spread and scale up services;Talk;Science,Psychotherapy;Integrate; andResearch excellence.
As an acronym, STSPIR.
Spread and scale up services: Spreading mental health services to uncovered areas, and increasing facilities in covered areas:Mental disorders are leading cause of ill health but bottom of health agenda;Patients face widespread discrimination, human rights violations and lack of facilities;Need to stem the brain drain from developing countries;At any given point, 10% of the adult population report having some mental or behavioural disorder;In India, serious mental disorders affect nearly 80 million people, i.e. combined population of the northern top of India, including Punjab, Haryana, Jammu and Kashmir, Uttarakhand and Himachal Pradesh;Combating imbalance between burden of demand and supply of efficient psychiatric services in all countries, especially in developing ones like India, is the first task before psychiatry today. If ever a greater role for activism were needed, this is the field;The need is to scale up effective and cost-effective treatments and preventive interventions for mental disorders.Talk: Speaking to a wider audience about positive contributions of psychiatry: Being aware of, understanding, and countering, the massive anti-psychiatry propaganda online and elsewhere;Giving a firm answer to anti-psychiatry even while understanding its transformation into mental health consumerism and opposition to reckless medicalisation;Defining normality and abnormality;Bringing about greater precision in diagnosis and care;Motivating those helped by psychiatry to speak up;Setting up informative websites and organising programmes to reduce stigma and spread mental health awareness;Setting up regular columns in psychiatry journals around the globe, called ‘Patients Speak’, or something similar, wherein those who have been helped get a chance to voice their stories.Science: Shrugging ambivalence and disagreement and searching for commonalities in psychiatric phenomena; An idiographic orientation which stresses individuality cannot, and should not, preclude the nomothetic or norm laying thrust that is the crux of scientific progress.The major contribution of science has been to recognize such commonalities so they can be researched, categorized and used for human welfare.It is a mistake to stress individuality so much that commonalities are obliterated.While the purpose and approach of psychiatry, as of all medicine, has to be humane and caring, therapeutic advancements and aetiologic understandings are going to result only from a scientific methodology.Just caring is not enough, if you have not mastered the methods of care, which only science can supply.Psychotherapy: Psychiatrists continuing to do psychotherapy: Psychotherapy must be clearly defined, its parameters and methods firmly delineated, its proof of effectiveness convincingly demonstrated by evidence based and controlled trials;Psychotherapy research suffers from neglect by the mainstream at present, because of the ascendancy of biological psychiatry;It suffers resource constraints as major sponsors like pharma not interested;Needs funding from some sincere researcher organisations and altruistic sponsors, as also professional societies and governments;Psychotherapy research will have to provide enough irrefutable evidence that it works, with replicable studies that prove it across geographical areas;It will not do for psychiatrists to hand over psychotherapy to clinical psychologists and others.Integrate approaches: Welcoming biological breakthroughs, while supplying psychosocial insights: Experimental breakthroughs, both in aetiology and therapeutics, will come mainly from biology, but the insights and leads can hopefully come from many other fields, especially the psychosocial and philosophical;The biological and the psychological are not exclusive but complementary approaches;Both integration and reductionism are valid. Integration is necessary as an attitude, reductionism is necessary as an approach. Both the biological and the psychosocial must co-exist in the individual psychiatrist, as much as the branch itself.Research excellence: Promoting genuine research alone, and working towards an Indian Nobel Laureate in psychiatry by 2020: To stop promoting poor quality research and researchers, and to stop encouraging sycophants and ladder climbers. To pick up and hone genuine research talent from among faculty and students;Developing consistent quality environs in departments and having Heads of Units who recognize, hone and nurture talent. And who never give in to pessimism and cynicism;Stop being satisfied with the money, power and prestige that comes by wheeling-dealing, groupism and politicking;Infinite vistas of opportunity wait in the wings to unfold and offer opportunities for unravelling the mysteries of the ‘mind’ to the earnest seeker. Provided he is ready to seek the valuable. Provided he stops holding on to the artificial and the superfluous.
PMCID: PMC4037900  PMID: 24891797
Biological breakthroughs; Commonalities in psychiatry; Indian Nobel Laureate; Integrate; Positive contributions of psychiatry; Psychosocial insights; Psychotherapy; Research excellence; Scale up services; Science; Stigma; Talk
7.  Cerebrovascular Smooth Muscle Actin Is Increased in Non-Demented Subjects with Frequent Senile Plaques at Autopsy: Implications for the Pathogenesis of Alzheimer Disease 
We previously found that vascular smooth muscle actin (SMA) is reduced in the brains of patients with late stage Alzheimer disease (AD) compared to brains of non-demented, neuropathologically normal subjects. To assess the pathogenetic significance and disease specificity of this finding, we studied 3 additional patient groups: non-demented subjects without significant AD type pathology (“Normal”, n = 20); non-demented subjects with frequent senile plaques at autopsy (“Preclinical AD”, n = 20); and subjects with frontotemporal dementia, (“FTD”, n = 10). The groups were matched for gender and age with those previously reported; SMA immunohistochemistry and image analysis were performed as previously described. Surprisingly, SMA expression in arachnoid, cerebral cortex and white matter arterioles was greater in the Preclinical AD group than in the Normal and FTD groups. The plaques were not associated with amyloid angiopathy or other vascular disease in this group. SMA expression in the brains of the Normal group was intermediate between the Preclinical AD and FTD groups. All 3 groups exhibited much greater SMA expression than in our previous report. The presence of frequent plaques and increased arteriolar SMA expression in the brains of non-demented subjects suggest that increased SMA expression might represent a physiologic response to neurodegeneration that could prevent or delay overt expression dementia in AD.
PMCID: PMC2732426  PMID: 19287310
Alzheimer disease; Arterioles; Demented subjects; Image analysis; Non-demented subjects; Smooth muscle actin
8.  Neuropathologic correlates of cognition in a population-based sample 
Many cognitively normal older adults have underlying neuropathologic changes of Alzheimer’s disease (AD), vascular brain injury (VBI), or Lewy body disease (LBD), which confer an increased risk of dementia. The current study focused on the association between multiple neuropathologic indices and performance on specific cognitive domains in a community sample of older adults. Of 438 participants in the Adult Changes in Thought population-based study of brain aging who were autopsied, 363 subjects had cognitive testing at their final study visit and were included. Associations were measured between performance on the Cognitive Abilities Screening Instrument prior to death and neuropathologic endpoints, including AD neuropathologic changes, LBD, cerebral amyloid angiopathy, and measures of VBI. Braak stage for neurofibrillary tangles, lower brain weight, and VBI as measured by cerebral cortical microvascular lesions (μVBI) explained a significant proportion of the variance associated with global cognitive test performance (R2=0.31, p< 0.0001) both in the entire sample and when analysis was restricted to non-demented subjects (R2= 0.23, p< 0.0001). Specific cognitive domains were differentially related to neuropathologic lesion type: memory and executive function with AD pathologic changes and cortical μVBI, executive function with subcortical μVBI, and visuospatial construction with LBD. Thus, neuropathologic lesions of LBD and μVBI are associated with poorer cognitive performance over and above AD neuropathologic changes in subjects without dementia in this cohort. These findings underscore that cognitive impairment is a complex convergent trait that has important implications for clinical investigation and medical management of older adults.
PMCID: PMC3737376  PMID: 23666176
Alzheimer’s disease; brain; cerebrovascular disorders; cognition; dementia; Lewy bodies; pathologic processes
9.  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.
PMCID: PMC3622231  PMID: 23596414
vascular dementia; vascular cognitive impairment; cerebral infarcts; large and small vessel disease; subcortical vascular lesions; neuropathology; pathogenic factors
10.  Mortality and incidence of cancer among a cohort of self employed butchers from Geneva and their wives. 
British Journal of Industrial Medicine  1993;50(11):1008-1016.
To investigate whether specific cancers are associated with the occupation of butcher, as has been reported from other countries, a historical prospective cohort study was undertaken. The cohort consisted of all self employed butchers (n = 552) and pork butchers (n = 310) born since 1880 who set up a shop in the canton of Geneva from 1901 to 1969, and of their wives (n = 887). The study group was followed up from 1901 to 1990 for general mortality, from 1942 to 1990 for cause specific mortality, and from 1970 to 1989 for incidence of cancer. There was no trace of 45 men (5%) and 52 women (6%). Compared with the general population of the canton of Geneva, butchers and pork butchers experienced a significant increase, taking into account 15 years of latency, in mortality from all causes (observed deaths (Obs) 540, expected deaths (Exp) 445.5, standardised mortality ratio (SMR) 121, 90% confidence interval (90% Cl) 113-130). There were significant excesses in incidence and mortality from colorectal cancer, cancer of the prostate, and all malignant neoplasms, and in incidence of cancer of the liver. The risk of lung cancer was significantly increased among pork butchers (SMR 176, 90% Cl 114-262; standardised incidence ratio (SIR) 231, 90% Cl 137-368) but not among butchers (SMR 92, 90% Cl 59-138; SIR 113, 90% Cl 67-179). There was also a significant increase in mortality from cancer of the larynx among butchers. For non-malignant causes of death significant excesses were found among all men for ischaemic heart disease, motor vehicle accidents, and cirrhosis of the liver. Analysis of subgroups showed a cluster of deaths from leukaemia among older butchers born between 1880 and 1899 (Obs 5, Exp 0.6, p < 0.0001). Exposure of pork butchers to polycyclic aromatic hydrocarbons during meat smoking, which was assessed in a contemporary study, might have contributed to their increased risk of lung cancer. The possible role of other factors, especially cigarette smoking, nitrosamines, and oncogenic viruses was discussed. Moreover, there was evidence from another contemporary study that butchers and pork butchers ate more animal fat, and probably more animal protein, than the average male population of Geneva. These results suggest that dietary factors could be implicated in the excesses of colorectal cancer, cancer of the prostate, and ischaemic heart disease. An increased risk for alcohol abuse might explain the excesses of liver cirrhosis, cancer of the liver, cancer of the larynx and motor vehicle accidents. Among all wives overall mortality was similar to that expected (SMR 100, 90% Cl 93-108) and there was no significant excess risk for any specific cancer nor for any non-malignant cause of death. Results for cancer of the cervix uteri, especially among subgroups, suggest an increased risk consistent with previous findings from other countries.
PMCID: PMC1035536  PMID: 8280626
11.  Nonsteroidal anti-inflammatory drugs are associated with increased neuritic plaques(e–Pub ahead of print) 
Neurology  2010;75(13):1203-1210.
Observational and experimental studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer disease (AD); however, clinical trials and other observational studies, including the Adult Changes in Thought (ACT) study, show no protection or promotion of AD. The objective of this study is to determine the relationship between common dementia-associated pathologies and mid- to late-life NSAID exposure.
We examined the association of mid- to late-life NSAID use with neuropathologic findings on 257 autopsies from ACT, a population-based study of brain aging and incident dementia. Cumulative standard daily doses (SDD) of nonselective NSAIDs were determined from ≥10 years of computerized pharmacy dispensing data. Analyses were adjusted for selection bias to broaden generalizability of results to 3,026 eligible participants in the ACT cohort. Seven pathologic indices were evaluated: intermediate or frequent score for neuritic plaques, Braak stages V or VI for neurofibrillary tangles, >2 cerebral microinfarcts, the presence of any neocortical Lewy bodies, any macroscopic infarcts, any amyloid angiopathy, and moderate or severe atherosclerosis.
Of the neuropathologic indices evaluated, only neuritic plaque score was significantly increased in participants with greater use of nonselective NSAIDs (p = 0.065), specifically in those with high levels of cumulative use: 1,000–2,000 SDD (adjusted relative risk [RR] 2.16, 95% confidence interval [CI] 1.02–4.25, compared to light/nonuse [<60 SDD]) and >2,000 SDD (adjusted RR 2.37, 95% CI 1.24–4.67).
Increased neuritic plaque accumulation may explain the association between heavy use of nonselective NSAIDs and increased risk of dementia among ACT participants.
= amyloid angiopathy;
= Adult Changes in Thought;
= Alzheimer disease;
= Consortium to Establish a Registry for Alzheimer's Disease;
= confidence interval;
= cerebral microinfarct;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= Group Health Cooperative;
= Lewy body disease;
= neurofibrillary tangle;
= neuritic plaque;
= nonsteroidal anti-inflammatory drug;
= over-the-counter;
= relative risk;
= standard daily dose;
= vascular brain injury.
PMCID: PMC3013492  PMID: 20811000
12.  Population studies of sporadic cerebral amyloid angiopathy and dementia: a systematic review 
BMC Neurology  2009;9:3.
Deposition of amyloid-β (Aβ) in vessel walls of the brain as cerebral amyloid angiopathy (CAA) could be a major factor in the pathogenesis of dementia. Here we investigate the relationship between dementia and the prevalence of CAA in older populations. We searched the literature for prospective population-based epidemiological clinicopathological studies, free of the biases of other sampling techniques, which were used as a comparison.
To identify population-based studies assessing CAA and dementia, a previous systematic review of population-based clinicopathological studies of ageing and dementia was employed. To identify selected-sample studies, PsychInfo (1806–April Week 3 2008), OVID MEDLINE (1950–April Week 2 2008) and Pubmed (searched 21 April 2008) databases were searched using the term "amyloid angiopathy". These databases were also employed to search for any population-based studies not included in the previous systematic review. Studies were included if they reported the prevalence of CAA relative to a dementia classification (clinical or neuropathological).
Four population-based studies were identified. They showed that on average 55–59% of those with dementia displayed CAA (of any severity) compared to 28–38% of the non-demented. 37–43% of the demented displayed severe CAA in contrast to 7–24% of the non-demented. There was no overlap in the range of these averages and they were less variable and lower than those reported in 38 selected sample studies (demented v non-demented: 32–100 v 0–77% regardless of severity; 0–50 v 0–11% for severe only).
CAA prevalence in populations is consistently higher in the demented as compared to the non-demented. This supports a significant role for CAA in the pathogenesis of dementia.
PMCID: PMC2647900  PMID: 19144113
13.  Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum 
Brain  2015;138(5):1370-1381.
Murray et al. examine the correspondence between Thal amyloid phase, tau pathology and clinical characteristics in a large Alzheimer’s disease autopsy series. They extrapolate their findings to an autopsy cohort for which Pittsburgh compound-B imaging data are available, and evaluate the neuropathological significance of a quantitative amyloid-β imaging cut-off point.
Murray et al. examine the correspondence between Thal amyloid phase, tau pathology and clinical characteristics in a large Alzheimer’s disease autopsy series. They extrapolate their findings to an autopsy cohort for which Pittsburgh compound-B imaging data are available, and evaluate the neuropathological significance of a quantitative amyloid-β imaging cut-off point.
Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer’s disease, was incorporated into the latest National Institute of Ageing – Alzheimer’s Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer’s disease dementia published by the National Institute of Ageing – Alzheimer’s Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem 11C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of 11C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. 11C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical 11C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer’s disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer’s disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted 11C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to 11C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer’s disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer’s disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with 11C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The 11C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1–2.
PMCID: PMC4407190  PMID: 25805643
Alzheimer’s disease; neuropathology; Thal amyloid phase; Pittsburgh compound B; Braak tangle stage
14.  A National Fragility Fractures Register 
In Italy, osteoporosis is a disease potentially affecting five million people, 80% of whom are post-menopausal women. The natural history of this disease culminates, dramatically, in fragility fractures. The incidence of fragility fractures is now reaching epidemic proportions and, indeed, can no longer be underestimated. In Italy, epidemiological data can be derived only from hospital discharge record (HDR)-based statistics supplied by the Ministry of Health. Since these records contain data relating only to patients discharged from hospitals and institutes providing inpatient care, they provide a figure much lower than the estimated 280,000+ new fractures every year. Despite the availability of these instruments, statistics on hospital admissions may be deemed reliable only in relation to the number of hip fractures, which in 2007 led to over 90,000 hospitalisations. Fragility fractures of other skeletal districts, on the other hand, are often treated non-invasively in the ER and therefore “slip through” the HDR net, leading to an absence of relative data, both as regards numbers and diagnoses. Data collected using the HDR system, which records information on the principal diagnosis (the reason treatment was needed and diagnostic investigations performed) and on secondary diagnoses (coexisting conditions at the time of hospital admission), constitute a resource for studying, assessing and planning admissions. This information, coded using the International Classification of Diseases 9 (ICD 9), is transmitted to regional authorities and then, by them, to the Ministry of Health. The ICD 9 classification is based on two main criteria: one is aetiological (the cause of the fracture) and the other anatomical (the site of the fracture); the latter is the one used most. In the case of fragility fractures, the presence of osteoporosis can be signalled only as a secondary diagnosis, thereby minimising its role in their pathogenesis. From this perspective, the limits of the classification system influence the definition of the real extent of fractures linked to bone fragility, therefore resulting in underestimation of the phenomenon. This separation of the fracture event from the diagnosis of osteoporosis means that the patient does not receive adequate treatment for the underlying disease.
In an attempt to resolve these problems, Italy’s present health minister, Ferruccio Fazio, on the occasion of the World Osteoporosis Day (October 20, 2009), unveiled a project to set up, with the collaboration of the Italian regions, a national fragility fracture register (NFFR), the only one in the world. Registers of this kind are instruments for the systematic collection, nationally, of the data needed to analyse the efficiency of processes and methods involved in health service provision to citizens. The NFFR will collect: demographic data, “process” outcomes (days of hospitalisation, treatments, timing of surgery, complications, types of discharge, etc.) and “final” outcomes (mortality, residual pain, functional recovery, residual disability, etc.). The data will be drawn from the HDRs of ordinary inpatient departments, from ER HDRs, from analyses of local health authority databases, and possibly from subsequent outcome surveys of quality of life and residual disability. There are plans to create a national data collection centre, to be run and coordinated by the Health Ministry, into which will be entered data from the regional registries. In this context, the aim of the NFFR is to establish the quality of interventions at regional and national level, to compare different local settings and identify areas where there is room for improvement in health service delivery, and to define reference standards of care, ranging from optimal to minimum acceptable standards. The NFFR will make it possible to establish more clearly the real extent of the problem and of its social and economic impact, allowing conditions of skeletal fragility to be reported, and thus adequately assessed and treated. The assigning of each individual patient with an alphanumerical code will be useful in the event of further interventions or re-fractures and for the creation of a risk card, a single unified card for collecting a patient’s history, that will be a further useful instrument for defining an individual’s bone fragility status. These further data could usefully complete the data collected in the NFFR, thereby improving the approach to and management of the multifaceted problem of fragile bones. It is necessary to promote a multidisciplinary approach to the patient, as well as the creation of “fragility fracture units”, an organisational model based on a pathway ensuring constant synergy between the different specialties involved in the care of the fracture patient. The NFFR will allow monitoring of the fragility fracture phenomenon so as to rationalise resources and monitor the efficacy of health policy interventions.
PMCID: PMC3213778
NeuroImage  2011;59(1):212-217.
Recent genetic and proteomic studies demonstrate that clusterin/apolipoprotein-J is associated with risk, pathology, and progression of Alzheimer’s disease (AD). Our main aim was to examine associations between plasma clusterin concentration and longitudinal changes in brain volume in normal aging and mild cognitive impairment (MCI). A secondary objective was to examine associations between peripheral concentration of clusterin and its concentration in the brain within regions that undergo neuropathological changes in AD. Non-demented individuals (N = 139; mean baseline age 70.5 years) received annual volumetric MRI (912 MRI scans in total) over a mean six-year interval. Sixteen participants (92 MRI scans in total) were diagnosed during the course of the study with amnestic MCI. Clusterin concentration was assayed by ELISA in plasma samples collected within a year of the baseline MRI. Mixed effects regression models investigated whether plasma clusterin concentration was associated with rates of brain atrophy for control and MCI groups and whether these associations differed between groups. In a separate autopsy sample of individuals with AD (N=17) and healthy controls (N=4), we examined the association between antemortem clusterin concentration in plasma and postmortem levels in the superior temporal gyrus, hippocampus and cerebellum. The associations of plasma clusterin concentration with rates of change in brain volume were significantly different between MCI and control groups in several volumes including whole brain, ventricular CSF, temporal gray matter as well as parahippocampal, superior temporal and cingulate gyri. Within the MCI but not control group, higher baseline concentration of plasma clusterin was associated with slower rates of brain atrophy in these regions. In the combined autopsy sample of AD and control cases, representing a range of severity in AD pathology, we observed a significant association between clusterin concentration in the plasma and that in the superior temporal gyrus. Our findings suggest that clusterin, a plasma protein with roles in amyloid clearance, complement inhibition and apoptosis, is associated with rate of brain atrophy in MCI. Furthermore, peripheral concentration of clusterin also appears to reflect its concentration within brain regions vulnerable to AD pathology. These findings in combination suggest an influence of this multi-functional protein on early stages of progression in AD pathology.
PMCID: PMC3425349  PMID: 21824521
clusterin; mild cognitive impairment (MCI); Alzheimer's disease (26); plasma; atrophy; biomarker
16.  Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias 
PLoS Genetics  2014;10(9):e1004606.
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.
Author Summary
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study (GWAS), as well as an analysis of known genetic risk loci for AD dementia, using data from 4,914 brain autopsies. Genome-wide significance was observed for 7 genes and pathologic features of AD and related diseases. Twelve of the 22 genetic risk loci for clinically-defined AD dementia were confirmed in our pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for hallmark pathologic features of AD were strongly positive and linear. Our study discovered new genetic associations with specific pathologic features and aligned known genetic risk for AD dementia with specific pathologic changes in a large brain autopsy study of AD and related dementias.
PMCID: PMC4154667  PMID: 25188341
17.  Mortality in Iraq Associated with the 2003–2011 War and Occupation: Findings from a National Cluster Sample Survey by the University Collaborative Iraq Mortality Study 
PLoS Medicine  2013;10(10):e1001533.
Based on a survey of 2,000 randomly selected households throughout Iraq, Amy Hagopian and colleagues estimate that close to half a million excess deaths are attributable to the recent Iraq war and occupation.
Please see later in the article for the Editors' Summary
Previous estimates of mortality in Iraq attributable to the 2003 invasion have been heterogeneous and controversial, and none were produced after 2006. The purpose of this research was to estimate direct and indirect deaths attributable to the war in Iraq between 2003 and 2011.
Methods and Findings
We conducted a survey of 2,000 randomly selected households throughout Iraq, using a two-stage cluster sampling method to ensure the sample of households was nationally representative. We asked every household head about births and deaths since 2001, and all household adults about mortality among their siblings. We used secondary data sources to correct for out-migration. From March 1, 2003, to June 30, 2011, the crude death rate in Iraq was 4.55 per 1,000 person-years (95% uncertainty interval 3.74–5.27), more than 0.5 times higher than the death rate during the 26-mo period preceding the war, resulting in approximately 405,000 (95% uncertainty interval 48,000–751,000) excess deaths attributable to the conflict. Among adults, the risk of death rose 0.7 times higher for women and 2.9 times higher for men between the pre-war period (January 1, 2001, to February 28, 2003) and the peak of the war (2005–2006). We estimate that more than 60% of excess deaths were directly attributable to violence, with the rest associated with the collapse of infrastructure and other indirect, but war-related, causes. We used secondary sources to estimate rates of death among emigrants. Those estimates suggest we missed at least 55,000 deaths that would have been reported by households had the households remained behind in Iraq, but which instead had migrated away. Only 24 households refused to participate in the study. An additional five households were not interviewed because of hostile or threatening behavior, for a 98.55% response rate. The reliance on outdated census data and the long recall period required of participants are limitations of our study.
Beyond expected rates, most mortality increases in Iraq can be attributed to direct violence, but about a third are attributable to indirect causes (such as from failures of health, sanitation, transportation, communication, and other systems). Approximately a half million deaths in Iraq could be attributable to the war.
Please see later in the article for the Editors' Summary
Editors' Summary
War is a major public health problem. Its health effects include violent deaths among soldiers and civilians as well as indirect increases in mortality and morbidity caused by conflict. Unlike those of other causes of death and disability, however, the consequences of war on population health are rarely studied scientifically. In conflict situations, deaths and diseases are not reliably measured and recorded, and estimating the proportion caused, directly or indirectly, by a war or conflict is challenging. Population-based mortality survey methods—asking representative survivors about deaths they know about—were developed by public health researchers to estimate death rates. By comparing death rate estimates for periods before and during a conflict, researchers can derive the number of excess deaths that are attributable to the conflict.
Why Was This Study Done?
A number of earlier studies have estimated the death toll in Iraq since the beginning of the war in March 2003. The previous studies covered different periods from 2003 to 2006 and derived different rates of overall deaths and excess deaths attributable to the war and conflict. All of them have been controversial, and their methodologies have been criticized. For this study, based on a population-based mortality survey, the researchers modified and improved their methodology in response to critiques of earlier surveys. The study covers the period from the beginning of the war in March 2003 until June 2011, including a period of high violence from 2006 to 2008. It provides population-based estimates for excess deaths in the years after 2006 and covers most of the period of the war and subsequent occupation.
What Did the Researchers Do and Find?
Interviewers trained by the researchers conducted the survey between May 2011 and July 2011 and collected data from 2,000 randomly selected households in 100 geographical clusters, distributed across Iraq's 18 governorates. The interviewers asked the head of each household about deaths among household members from 2001 to the time of the interview, including a pre-war period from January 2001 to March 2003 and the period of the war and occupation. They also asked all adults in the household about deaths among their siblings during the same period. From the first set of data, the researchers calculated the crude death rates (i.e., the number of deaths during a year per 1,000 individuals) before and during the war. They found the wartime crude death rate in Iraq to be 4.55 per 1,000, more than 50% higher than the death rate of 2.89 during the two-year period preceding the war. By multiplying those rates by the annual Iraq population, the authors estimate the total excess Iraqi deaths attributable to the war through mid-2011 to be about 405,000. The researchers also estimated that an additional 56,000 deaths were not counted due to migration. Including this number, their final estimate is that approximately half a million people died in Iraq as a result of the war and subsequent occupation from March 2003 to June 2011.
The risk of death at the peak of the conflict in 2006 almost tripled for men and rose by 70% for women. Respondents attributed 20% of household deaths to war-related violence. Violent deaths were attributed primarily to coalition forces (35%) and militia (32%). The majority (63%) of violent deaths were from gunshots. Twelve percent were attributed to car bombs. Based on the responses from adults in the surveyed households who reported on the alive-or-dead status of their siblings, the researchers estimated the total number of deaths among adults aged 15–60 years, from March 2003 to June 2011, to be approximately 376,000; 184,000 of these deaths were attributed to the conflict, and of those, the authors estimate that 132,000 were caused directly by war-related violence.
What Do These Findings Mean?
These findings provide the most up-to-date estimates of the death toll of the Iraq war and subsequent conflict. However, given the difficult circumstances, the estimates are associated with substantial uncertainties. The researchers extrapolated from a small representative sample of households to estimate Iraq's national death toll. In addition, respondents were asked to recall events that occurred up to ten years prior, which can lead to inaccuracies. The researchers also had to rely on outdated census data (the last complete population census in Iraq dates back to 1987) for their overall population figures. Thus, to accompany their estimate of 460,000 excess deaths from March 2003 to mid-2011, the authors used statistical methods to determine the likely range of the true estimate. Based on the statistical methods, the researchers are 95% confident that the true number of excess deaths lies between 48,000 and 751,000—a large range. More than two years past the end of the period covered in this study, the conflict in Iraq is far from over and continues to cost lives at alarming rates. As discussed in an accompanying Perspective by Salman Rawaf, violence and lawlessness continue to the present day. In addition, post-war Iraq has limited capacity to re-establish and maintain its battered public health and safety infrastructure.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Salman Rawaf.
The Geneva Declaration on Armed Violence and Development website provides information on the global burden of armed violence.
The International Committee of the Red Cross provides information about war and international humanitarian law (in several languages).
Medact, a global health charity, has information on health and conflict.
Columbia University has a program on forced migration and health.
Johns Hopkins University runs the Center for Refugee and Disaster Response.
University of Washington's Health Alliance International website also has information about war and conflict.
PMCID: PMC3797136  PMID: 24143140
18.  An elevated D-dimer value: a burden on our patients and hospitals 
With 200,000 annual deaths in the United States due to pulmonary embolism (PE), efficient and accurate diagnosis is mandatory. Since negative D-dimer values are only useful in ruling out PE, elevated values alone should not result in excessive testing. This study assessed the diagnostic and financial yield of the D-dimer in diagnosing PE. This retrospective review of 220 medical records of patients at a South Chicago Community Hospital explored the extent of the work-up following an elevated D-dimer for a suspected PE. Patients were randomly selected with no exclusion criteria. Five of the 118 (4.2%) patients with elevated D-dimer values were diagnosed with a PE. Tests ordered based on elevated D-dimer values were billed for more than $200,000. The current diagnostic approach has been medically and financially inefficient. Patients should not be worked-up for a PE based primarily on an elevated D-dimer value. Two prominent factors, independent of PE, that result in elevated D-dimer values and were pertinent to the studied population, are age and African-American origin. Implementing a scoring system, like the revised-Geneva scale, will establish a better index of suspicion to improve both the physician’s diagnostic approach and the yield of the work-up.
PMCID: PMC3273370  PMID: 22319245
pulmonary embolism; D-dimer; diagnosis; age; African-Americans; scoring
19.  Neuropathologic assessment of participants in two multi-center longitudinal observational studies: the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN) 
It has been hypothesized that the relatively rare autosomal dominant Alzheimer disease (ADAD) may be a useful model of the more frequent, sporadic, late-onset AD (LOAD). Individuals with ADAD have a predictable age at onset and the biomarker profile of ADAD participants in the preclinical stage may be used to predict disease progression and clinical onset. However, the extent to which the pathogenesis and neuropathology of ADAD overlaps with that of LOAD is equivocal. To address this uncertainty, two multicenter longitudinal observational studies, the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN), leveraged the expertise and resources of the existing Knight Alzheimer Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, Missouri, USA, to establish a Neuropathology Core (NPC). The ADNI/DIAN-NPC is systematically examining the brains of all participants who come to autopsy at the 59 ADNI sites in the USA and Canada and the 14 DIAN sites in the USA (8), Australia (3), UK (1), and Germany (2). By 2014, 41 ADNI and 24 DIAN autopsies (involving 9 participants and 15 family members) had been performed. The autopsy rate in the ADNI cohort in the most recent year was 93% (total since NPC inception: 70%). In summary, the ADNI/DIAN NPC has implemented a standard protocol for all sites to solicit permission for brain autopsy and to send brain tissue to the NPC for a standardized, uniform, and state-of-the-art neuropathologic assessment. The benefit to ADNI and DIAN of the implementation of the NPC is very clear. The NPC provides final ‘gold standard’ neuropathological diagnoses and data against which the antecedent observations and measurements of ADNI and DIAN can be compared.
PMCID: PMC4521391  PMID: 25964057
Autosomal dominant; Alzheimer disease; Late-onset Alzheimer disease; neuropathologic diagnostic criteria; neuropathologic heat map; PET-PiB amyloid imaging
20.  Improving the Proteomic Analysis of Archival Tissue by Using Pressure-Assisted Protein Extraction: A Mechanistic Approach 
Formaldehyde-fixed, paraffin-embedded (FFPE) tissue repositories represent a valuable resource for the retrospective study of disease progression and response to therapy. However, the proteomic analysis of FFPE tissues has been hampered by formaldehyde-induced protein modifications, which reduce protein extraction efficiency and may lead to protein misidentification. Here, we demonstrate the use of heat augmented with high hydrostatic pressure (40,000 psi) as a novel method for the recovery of intact proteins from FFPE tissue. Our laboratory has taken a mechanistic approach to developing improved protein extraction protocols, by first studying the reactions of formaldehyde with proteins and ways to reverse these reactions, then applying this approach to a model system called a “tissue surrogate”, which is a gel formed by treating high concentrations of cytoplasmic proteins with formaldehyde, and finally FFPE mouse liver tissue. Our studies indicate that elevated pressure improves the recovery of proteins from FFPE tissue surrogates by hydrating and promoting solubilization of highly aggregated proteins allowing for the subsequent reversal (by hydrolysis) of formaldehyde-induced protein adducts and cross-links. When FFPE mouse liver was extracted using heat and elevated pressure, there was a 4-fold increase in protein extraction efficiency and up to a 30-fold increase in the number of non-redundant proteins identified by mass spectrometry, compared to matched tissue extracted with heat alone. More importantly, the number of non-redundant proteins identified in the FFPE tissue was nearly identical to that of the corresponding frozen tissue.
PMCID: PMC4103194  PMID: 25049470
Antigen Retrieval; FFPE; Formalin-fixed paraffin-embedded; High-pressure protein extraction; Mass spectrometry; Proteomics
21.  Human erythrocyte myosin: identification and purification 
The Journal of Cell Biology  1985;100(1):47-55.
Human erythrocytes contain an Mr 200,000 polypeptide that cross-reacts specifically with affinity-purified antibodies to the Mr 200,000 heavy chain of human platelet myosin. Immunofluorescence staining of formaldehyde-fixed erythrocytes demonstrated that the immunoreactive myosin polypeptide is present in all cells and is localized in a punctate pattern throughout the cell. Between 20-40% of the immunoreactive myosin polypeptide remained associated with the membranes after hemolysis and preparation of ghosts, suggesting that it may be bound to the membrane cytoskeleton as well as being present in the cytosol. The immunoreactive myosin polypeptide was purified from the hemolysate to approximately 85% purity by DEAE-cellulose chromatography followed by gel filtration on Sephacryl S-400. The purified protein is an authentic vertebrate myosin with two globular heads at the end of a rod-like tail approximately 150-nm long, as visualized by rotary shadowing of individual molecules, and with two light chains (Mr 25,000 and 19,500) in association with the Mr 200,000 heavy chain. Peptide maps of the Mr 200,000 heavy chains of erythrocyte and platelet myosin were seen to be nearly identical, but the proteins are distinct since the platelet myosin light chains migrate differently on SDS gels (Mr 20,000 and 17,000). The erythrocyte myosin formed bipolar filaments 0.3-0.4-micron long at physiological salt concentrations and exhibited a characteristic pattern of myosin ATPase activities with EDTA, Ca++, and Mg++-ATPase activities in 0.5 M KCl of 0.38, 0.48, and less than 0.01 mumol/min per mg. The Mg++-ATPase activity of erythrocyte myosin in 0.06 M KCl (less than 0.01 mumol/min per mg) was not stimulated by the addition of rabbit muscle F-actin. The erythrocyte myosin was present in about 6,000 copies per cell, in a ratio of 80 actin monomers for every myosin molecule, which is an amount comparable to actin/myosin ratios in other nonmuscle cells. The erythrocyte myosin could function together with tropomyosin on the erythrocyte membrane (Fowler, V.M., and V. Bennett, 1984, J. Biol. Chem., 259:5978-5989) in an actomyosin contractile apparatus responsible for ATP-dependent changes in erythrocyte shape.
PMCID: PMC2113489  PMID: 3880759
22.  Excessive S-Adenosyl-L-Methionine-Dependent Methylation Increases Levels of Methanol, Formaldehyde and Formic Acid in Rat Brain Striatal Homogenates: Possible role in S-adenosyl-L-methionine-induced Parkinson’s disease-like disorders 
Life sciences  2008;83(25-26):821-827.
Excessive methylation may be a precipitating factor for Parkinson’s disease (PD) since S-adenosylmethionine (SAM), the endogenous methyl donor, induces PD-like changes when injected into the rat brain. The hydrolysis of the methyl ester bond of the methylated proteins produces methanol. Since methanol is oxidized into formaldehyde, and formaldehyde into formic acid in the body, we investigated the effects of SAM on the production of methanol, formaldehyde and formic acid in rat brain striatal homogenates and the toxicity of these products in PC12 cells.
Main methods
radio-enzymatic and colorimetric assays, cell viability, Western blot.
Key findings
SAM increased the formation of methanol, formaldehyde and formic acid in a concentration and time-dependent manner. Concentrations of [3H-methyl]-SAM at 0.17, 0.33, 0.67 and 1.34 nM produced 3.8, 8.0, 18.3 and 34.4 fmol/mg protein/h of [3H] methanol in rat striatal homogenates, respectively. SAM also significantly generated formaldehyde and formic acid in striatal homogenates. Formaldehyde was the most toxic metabolite to differentiated PC12 pheochromocytoma cells in cell culture studies, indicating that formaldehyde formed endogenously may contribute to neuronal damage in excessive methylation conditions. Subtoxic concentration of formaldehyde decreased the expression of tyrosine hydroxylase, the limiting factor in dopamine synthesis. Formaldehyde was more toxic to catecholaminergic PC12 cells than C6 glioma cells, indicating that neurons are more vulnerable to formaldehyde than glia cells.
We suggest that excessive carboxylmethylation of proteins might be involved in the SAM-induced PD-like changes and in the aging process via the toxic effects of formaldehyde.
PMCID: PMC2885904  PMID: 18930743
Parkinson’s disease; protein methylation; tyrosine-hydroxylase; PC12 cells
23.  Caspase-cleaved TAR DNA-binding protein-43 in Pick’s disease 
The hyperphosphorylation and proteolytic modification of the TAR DNA binding protein-43 (TDP-43) is a key finding in a number of neurodegenerative diseases including frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U), amyotrophic lateral sclerosis (ALS), and most recently Alzheimer’s disease (AD). To examine whether proteolytic modifications of TDP-43 is a relevant finding in Pick’s disease, we utilized a novel site-directed caspase-cleavage antibody based upon a known caspase-3 cleavage consensus site within TDP-43 at position 219. Application of this antibody, termed TDP caspase-cleavage product (TDPccp) to postmortem Pick’s disease brain sections revealed the presence of caspase-cleaved TDP-43 in Pick and Hirano bodies predominantly within region CA1 of the hippocampus. Co-localization of TDPccp with PHF-1, a general marker for Pick bodies, as well as with an antibody to caspase-cleaved tau (TauC3) was evident within the hippocampus. A semi-quantitative analysis indicated that approximately 21% and 79% of the Pick bodies identified in area CA1 contained caspase-cleaved TDP-43 or caspase-cleaved tau, respectively. Of interest was the lack of co-localization of TDPccp with PHF-1 in Pick bodies within the dentate gyrus. Collectively, these data have identified modified TDP-43 as a component of Pick and Hirano bodies that is restricted to area CA1 in Pick’s disease. The relative paucity of caspase-cleaved TDP-43 found within Pick bodies in comparison to caspase-cleaved tau suggests that TDP-43 and its modification by caspases is most likely not a contributing factor leading to Pick body formation.
PMCID: PMC2856940  PMID: 20411029
Pick’s disease; Pick bodies; caspases; TDP-43; Hirano bodies; tau
24.  Alzheimer pathology does not mediate the association between depressive symptoms and subsequent cognitive decline 
Depressive symptoms in non-demented persons appear to hasten the conversion from Mild Cognitive Impairment (MCI) to clinical Alzheimer's disease (AD) and doubles the risk of incident AD. However, the mechanism(s) by which depression might effect this risk has not been well established. The purpose of this analysis is to test the hypothesis that progression of AD pathology mediates depression's apparent effect on the risk of dementia conversion using longitudinally collected psychometric testing and autopsy data from the Honolulu-Asia Aging Study (HAAS).
Latent factor variables representing AD, cortical Lewy body (CLB) and ischemic neuropathology were tested as potential mediators of the Centers for Epidemiological Studies depression scale (CES-D)'s significant association with the 10-year prospective rate of cognitive decline, adjusted for baseline cognition, age, education, total number of medications and brain weight at autopsy.
CES-D scores, neurofibrillary tangle (NFT) counts, CLB counts and ischemic lesions each made significant independent contributions to cognitive decline. However, CES-D scores were not significantly associated with any pathological variable, which thus were not mediators of its effect.
We can confirm that subsyndromal depressive symptoms are significantly associated with subsequent cognitive decline. Although the effect is relatively modest, it is stronger than that of amyloid-related neuropathologies, and independent of that of NFT, CLB and ischemic lesions. Our results argue against AD-related neuropathology as a mediator of depression's effects on cognitive decline, but cannot rule out a significant mediation effect in a subset of cases, perhaps with greater baseline depressive symptoms.
PMCID: PMC4459124  PMID: 23154050
aging; Alzheimer's; depression; dementia; longitudinal; neuropathology
25.  Neuropathological basis of age-associated brain atrophy 
JAMA neurology  2013;70(5):616-622.
To examine the association between brain atrophy during life and neuropathology in an elderly population.
Cohort study of community dwelling elderly
Seventy-one healthy elderly were selected from participants of the Oregon Brain Aging Study for having an autopsy, >1 MRI scan and the last MRI scan within 36 months of death.
The associations between brain volume trajectories (ventricular, total brain and hippocampal) and time interaction terms for neurofibrillary tangles (NFTs), neuritic plaques (NPs), gross infarcts, microinfarcts, amyloid angiopathy, Lewy bodies, APOE ε4 presence, and clinical diagnosis (no cognitive impairment, mild cognitive impairment (MCI) and dementia, as time varying covariates) were examined in mixed effects models, adjusting for duration of follow up and age at death.
Ventricular volume trajectory was significantly associated with age, presence of infarcts, NFT and NP scores, the ε4 allele and dementia diagnosis. Total brain volume trajectory was significantly associated with age, and MCI diagnosis. Hippocampal volume trajectory was significantly associated with amyloid angiopathy.
Ventricular volume trajectory is more sensitive than total brain and hippocampal volume trajectories as a marker of accruing Alzheimer disease and vascular pathology in elderly individuals. The association between brain volume trajectories and cognitive impairment (MCI and dementia) remained after controlling for the degree of neuropathology and other covariates. This suggests that there may be other factors, not measured in this study that may be contributing to brain atrophy in those with cognitive impairment.
PMCID: PMC3898525  PMID: 23552688
Alzheimer’s disease; volumetric MRI; cohort studies

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