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.
Alzheimer's disease; Alzheimer's Disease Neuroimaging Initiative; autopsy consent; brain bank; neuropathologic diagnostic criteria
PICK1 (protein interacting with C-kinase 1) is a peripheral membrane protein with high expression in brain, testis, pancreas and other neuroendocrine tissues. Male Pick1 knockout mice are completely infertile, with a phenotype resembling the human disease globozoospermia. Since PICK1 is expressed in both testis and neuroendocrine tissues, infertility of Pick1 knockout mice may be due to either impaired neuroendocrine function or abnormal spermatogenesis. To distinguish these two possibilities, we restored PICK1's expression in the testis by seminiferous tubule microinjection of PICK1-containing lentivirus. By examining the testis-specific Pick1 transgenic mice, we found that PICK1's expression in testis rescued the spermatogenic abnormalities and male infertility in Pick1 knockout mice. Our results indicate that the infertility is caused by the lack of PICK1 in the testis rather than in other organs. In addition, we found that seminiferous tubule microinjection of lentivirus has a strong preference to produce testis-specific transgenic mice.
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.
Alzheimer’s disease; brain; cerebrovascular disorders; cognition; dementia; Lewy bodies; pathologic processes
Recent reports of a potentially increased risk of amyotrophic lateral sclerosis (ALS) for veterans deployed to the 1990–1991 Persian Gulf War prompted the Department of Veterans Affairs to establish a National Registry of Veterans with ALS, charged with the goal of enrolling all US veterans with a neurologist-confirmed diagnosis of ALS. The Genes and Environmental Exposures in Veterans with ALS study (GENEVA) is a case-control study presently enrolling cases from the Department of Veterans Affairs registry and a representative sample of veteran controls to evaluate the joint contributions of genetic susceptibility and environmental exposures to the risk of sporadic ALS. The GENEVA study design, recruitment strategies, methods of collecting DNA samples and environmental risk factor information are described here, along with a summary of demographic characteristics of the participants (537 cases, 292 controls) enrolled to date.
Amyotrophic lateral sclerosis, case-control study; GENEVA study recruitment methods; Gene-environment interaction
Autopsy evaluation of the brain of a patient with frontotemporal dementia (FTD) can be daunting to the general pathologist. At some point in their training, most pathologists learn about Pick disease, and can recognize Pick bodies, the morphologic hallmark of Pick disease. Pick disease is a type of frontotemporal lobar degeneration (FTLD), the general category of pathologic process underlying most cases of FTD. The 2 major categories of pathologic FTLD are tauopathies (FTLD-tau) and ubiquitinopathies (FTLD-U). Pick disease is one of the FTLD-tau subtypes and is termed FTLD-tau (PiD).
To “demystify” FTLDs, and to demonstrate that subtypes of FTLD-tau and FTLD-U can be easily determined by following a logical, stepwise, histochemical, and immunohistochemical investigation of the FTD autopsy brain.
Previously published peer-reviewed articles.
The hope is that this article will be a useful reference for the general pathologist faced with performing a brain autopsy on a decedent with frontotemporal dementia.
Postmortem human brain is a valuable resource for studying the neuropathology, neurochemistry, and molecular pathways of genes associated with bipolar disorder (BPD), yet available well-characterized BPD brain tissue appears scarce. We set out to evaluate BPD postmortem brain collections in order to identify both successful methods as well as barriers to collection.
We conducted a literature review of postmortem studies of BPD over the past 30 years, compared and contrasted characteristics of established BPD collections, and identified possible barriers specific to BPD brain collection based on our experience at the NIMH Brain Collection.
Currently, 80% of postmortem BPD studies were derived from just two brain repositories worldwide: the Stanley Brain Collection (69%) and Harvard Brain Tissue Resource Center (HBTRC) (11%) (Combined subjects n=72). The NIMH Brain Collection collected BPD cases four times less frequently than cases with schizophrenia, despite similar prevalence rates for these disorders. Only 53% of cases referred to the NIMH collection as BPD met DSM-IV criteria, with inadequate documentation and comorbid substance abuse as primary confounds for diagnosis in the remaining 47% of cases.
Accurate identification and diagnosis of BPD is a central obstacle to BPD brain collection. Comorbid substance abuse and manner of death are two of many critical factors to consider in BPD postmortem studies. Difficulties in BPD brain collection, coupled with the cessation of brain collection by the Stanley Brain Collection, make the need for alternative BPD brain sources imperative. Recommendations for future BPD tissue collection are offered.
bipolar disorder; brain; postmortem; Stanley Foundation Neuropathology Consortium; Stanley Array Collection; Harvard Brain Tissue Resource Center; NIMH Brain Collection
Recent reports of a potentially increased risk of amyotrophic lateral sclerosis (ALS) for veterans deployed to the 1990-91 Persian Gulf War prompted the Department of Veterans Affairs to establish a National Registry of Veterans with ALS, charged with the goal of enrolling all US veterans with a neurologist-confirmed diagnosis of ALS (Allen et al., this issue). The GENEVA study (Genes and Environmental Exposures in Veterans with ALS) is a case-control study presently enrolling cases from the VA registry and a representative sample of veteran controls to evaluate the joint contributions of genetic susceptibility and environmental exposures to the risk of sporadic ALS. The GENEVA study design, recruitment strategies, and methods of collecting DNA samples and environmental risk factor information are described here, along with a summary of demographic characteristics of the participants (537 cases, 292 controls) enrolled to date.
case-control study; recruitment methods; gene-environment interaction
Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 344 non-demented subjects with autopsy (201 subjects with low and 143 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided genome-wide significant evidence that variants in the RELNgene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia.
This article aims to explain the reasons for the remarkable change in age of breast cancer occurrence in the Swiss canton of Geneva.
We used population-based data from the Geneva cancer registry, which collects information on method of detection, stage and tumour characteristics since 1975. For patients diagnosed between 1997–2003, we obtained additional information on use of hormone replacement therapy from a large prospective study on breast cancer. Using generalized log linear regression analysis, we compared age-specific incidence rates with respect to period, stage, oestrogen receptor status, method of detection and use of hormone replacement therapy.
In the periods 1975–1979 and 1985–1989, breast cancer risk increased with age, showing the highest incidence rates among women aged ≥ 85 years. From 1997, the age-specific incidence curve changed completely (p < 0.0001), showing an incidence peak at 60–64 years and a reduced incidence among elderly women. This incidence peak concerned mainly early stage and oestrogen positive cancers and was exclusively observed among women who ever used hormone replacement therapy, regardless whether the tumour was screen-detected or not.
The increasing prevalence of hormone replacement therapy use during the 1990s could explain the important change in age-specific breast cancer incidence, not only by increasing breast cancer risk, but also by revealing breast cancer at an earlier age.
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.
Alzheimer disease; Arterioles; Demented subjects; Image analysis; Non-demented subjects; Smooth muscle actin
A necropsy study of 159 elderly patients drawn mainly from a prospectively assessed geriatric hospital population was carried out to investigate the relationship of cerebral amyloid angiopathy to Alzheimer's disease, other CNS disease and ageing. About half the patients were demented and the majority of these had Alzheimer's disease. In Alzheimer's disease there was an incidence of cerebral amyloid angiopathy of 82%. Among the other groups of patients, both demented and non-demented, the incidence of cerebral amyloid angiopathy was a little over 30%, and remained constant between 60 and 102 years of age.
Key pathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1) nonagenarians with AD and a high amyloid plaque load; 2) nonagenarians with no dementia and a high amyloid plaque load; 3) nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND) group (average age 71 years) with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular “dysfunction” compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD.
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.
radio-enzymatic and colorimetric assays, cell viability, Western blot.
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.
Parkinson’s disease; protein methylation; tyrosine-hydroxylase; PC12 cells
Ian Fraser died at his residence, 19 Upper Malone Road, on 11th May in his ninety-ninth year. He had been a significant force in Ulster surgery, indeed the entire Ulster medical scene, almost from his appointment as an ‘honorary attending surgeon in charge of the out-patient department’ at the then Belfast Hospital for Sick Children (in Queen Street) in 1927 until late in life; and he was to receive wide national and international recognition. An acute sense of history was not the least of his gifts and all writers on local medical history owe much to his perceptive sketches of predecessors and earlier contemporaries.
A memorial service was held in Fisherwick Church on 2nd July. The family honoured me in their invitation to give a Tribute - which is reproduced below. I have added some notes which with standard reference sources, Ian's own autobiographical sketches, the Fraser Archive in the Archivist's office at RVH and other material preserved by his son, will I hope, provide sufficient background information to tempt the future biographer whom Fraser's life so richly deserves.
The Asian bush mosquito, Aedes japonicus japonicus, a potential vector of several viruses, was first detected in Germany in 2008 on the Swiss-German border. In the following years, this invasive species apparently succeeded in establishing populations in southern Germany and in spreading northwards. In 2011, its distribution area already covered large areas of the federal state of Baden-Wurttemberg, and its northernmost German collection point was reported to be close to Stuttgart. Several independent submissions to our laboratories of Ae. j. japonicus specimens in July 2012, originating from the same area in the federal state of North Rhine-Westphalia, western Germany, prompted us to carry out an immediate surveillance in this region in the expectation of finding a further distribution focus of Ae. j. japonicus in Germany.
After inspecting the places of residence of the collectors of the submitted mosquito specimens, all kinds of water containers in 123 cemeteries in surrounding towns and villages were checked for mosquito developmental stages. These were collected and kept to produce adults for morphological species identification. One specimen per collection site was identified genetically by COI sequence analysis.
Aedes j. japonicus adults and immature stages were found in 36 towns/villages that were checked (29%) over an area of approximately 2,000 km2 in southern North Rhine-Westphalia and northern Rhineland Palatinate. The species could not be demonstrated further south when monitoring towards the northernmost previous collection sites in southern Germany. It therefore remains to be elucidated whether the species has entered western Germany from the south, from Belgium in the west where it has been demonstrated to occur locally since 2002, or through a new introduction.
Aedes j. japonicus is obviously much more widely distributed in Germany than previously thought. It appears to be well adapted, to have a strong expansion tendency and to replace indigenous mosquito species. Thus, a further spread is anticipated and elimination seems hardly possible anymore. The vector potency of the species should be reason enough to thoroughly monitor its future development in Germany.
Aedes japonicus japonicus; Cemeteries; Distribution focus; Spread; Western Germany
Many reports have described that there are fewer differences in AD brain neuropathologic lesions between AD patients and control subjects aged 80 years and older, as compared with the considerable differences between younger persons with AD and controls. In fact some investigators have suggested that since neurofibrillary tangles (NFT) can be identified in the brains of non-demented elderly subjects they should be considered as a consequence of the aging process. At present, there are no universally accepted neuropathological criteria which can mathematically differentiate AD from healthy brain in the oldest old.
The aim of this study is to discover the hidden and non-linear associations among AD pathognomonic brain lesions and the clinical diagnosis of AD in participants in the Nun Study through Artificial Neural Networks (ANNs) analysis
The analyses were based on 26 clinically- and pathologically-confirmed AD cases and 36 controls who had normal cognitive function. The inputs used for the analyses were just NFT and neuritic plaques counts in neocortex and hippocampus, for which, despite substantial differences in mean lesions counts between AD cases and controls, there was a substantial overlap in the range of lesion counts.
By taking into account the above four neuropathological features, the overall predictive capability of ANNs in sorting out AD cases from normal controls reached 100%. The corresponding accuracy obtained with Linear Discriminant Analysis was 92.30%. These results were consistently obtained in ten independent experiments. The same experiments were carried out with ANNs on a subgroup of 13 non severe AD patients and on the same 36 controls. The results obtained in terms of prediction accuracy with ANNs were exactly the same.
Input relevance analysis confirmed the relative dominance of NFT in neocortex in discriminating between AD patients and controls and indicated the lesser importance played by NP in the hippocampus.
The results of this study suggest that: a) cortical NFT represent the key variable in AD neuropathology; b) the neuropathologic profile of AD subjects is complex, however, c) ANNs can analyze neuropathologic features and differentiate AD cases from controls.
A common weakness of patient satisfaction surveys is a suboptimal participation rate. Some patients may be unable to participate, because of language barriers, physical limitations, or mental problems. As the role of these barriers is poorly understood, we aimed to identify patient characteristics that are associated with non-participation in a patient satisfaction survey.
At the University Hospitals of Geneva, Switzerland, a patient satisfaction survey is regularly conducted among all adult patients hospitalized for >24 hours on a one-month period in the departments of internal medicine, geriatrics, surgery, neurosciences, psychiatry, and gynaecology-obstetrics. In order to assess the factors associated with non-participation to the patient satisfaction survey, a case-control study was conducted among patients selected for the 2005 survey. Cases (non respondents, n = 195) and controls (respondents, n = 205) were randomly selected from the satisfaction survey, and information about potential barriers to participation was abstracted in a blinded fashion from the patients' medical and nursing charts.
Non-participation in the satisfaction survey was independently associated with the presence of a language barrier (odds ratio [OR] 4.53, 95% confidence interval [CI95%]: 2.14–9.59), substance abuse (OR 3.75, CI95%: 1.97–7.14), cognitive limitations (OR 3.72, CI95%: 1.64–8.42), a psychiatric diagnosis (OR 1.99, CI95%: 1.23–3.23) and a sight deficiency (OR 2.07, CI95%: 0.98–4.36). The odds ratio for non-participation increased gradually with the number of predictors.
Five barriers to non-participation in a mail survey were identified. Gathering patient feedback through mailed surveys may lead to an under-representation of some patient subgroups.
The neuropathological examination is considered to provide the gold standard for Alzheimer disease (AD). To determine the accuracy of currently employed clinical diagnostic methods, clinical and neuropathological data from the National Alzheimer's Coordinating Center (NACC), which gathers information from the network of National Institute on Aging (NIA)-sponsored Alzheimer's Disease Centers (ADCs), were collected as part of the NACC Uniform Data Set (UDS) between 2005 and 2010. A database search initially included all 1198 subjects with at least one UDS clinical assessment and who had died and been autopsied; 279 were excluded as being not demented or because critical data fields were missing. The final subject number was 919. Sensitivity and specificity were determined based on “probable” and “possible” AD levels of clinical confidence and 4 levels of neuropathological confidence based on varying neuritic plaque densities and Braak neurofibrillary stages. Sensitivity ranged from 70.9% to 87.3%; specificity ranged from 44.3% to 70.8%. Sensitivity was generally increased with more permissive clinical criteria and specificity was increased with more restrictive criteria, whereas the opposite was true for neuropathological criteria. When a clinical diagnosis was not confirmed by minimum levels of AD histopathology, the most frequent primary neuropathological diagnoses were tangle-only dementia or argyrophilic grain disease, frontotemporal lobar degeneration, cerebrovascular disease, Lewy body disease and hippocampal sclerosis. When dementia was not clinically diagnosed as AD, 39% of these cases met or exceeded minimum threshold levels of AD histopathology. Neurologists of the NIA-ADCs had higher predictive accuracy when they diagnosed AD in demented subjects than when they diagnosed dementing diseases other than AD. The misdiagnosis rate should be considered when estimating subject numbers for AD studies, including clinical trials and epidemiological studies.
Alzheimer disease; Autopsy; Clinical trials; Diagnosis; Histopathology; Neuropathology; Non-Alzheimer dementia
Reports of false beliefs may be a unique feature of behavioral variant frontotemporal dementia (bvFTD) but the nature of these experiences is unclear.
To report a case of pathologically verified Pick disease in a patient presenting with prominent and recurrent fantasies.
We describe the clinical, neuroradiologic, and neuropathologic findings of a 53-year-old woman presenting with fantasies and meeting Clinical Consensus Criteria for bvFTD.
Early in her course, she reported interactions with different actors, having torrid affairs with them, and other related fantasies. When confronted with her false beliefs, she admitted that these relationships were imaginary. Autopsy revealed Pick disease with τ-immunoreactive Pick bodies in the frontal and temporal cortices, and in the hippocampi.
Fantastic thinking, or vividly experienced imagination, may be a manifestation of bvFTD that is distinct from delusions and confabulations and could be the source of previously reported delusions and confabulations in bvFTD.
frontotemporal dementia; Pick disease; confabulations; delusions; fantasy
Seven cases of lobar cerebral haemorrhage due to amyloid angiopathy were found among 60 necropsy cases of intracerebral haemorrhage. Clinically five patients were demented and two had hypertension. Immediately after the onset of stroke there was a high incidence of headache and vomiting, followed by nuchal rigidity. Amyloid angiopathy was most prominent in the cerebral cortex and the leptomeninges. Senile plaques were noted in all cases. One should suspect that a haemorrhage may be due to amyloid angiopathy, when lobar cerebral haemorrhage occurs in an aged, normotensive patient with or without dementia. Surgical evacuation of the haematoma is inadvisable, because of the diffuse nature of amyloid angiopathy, high recurrence rate and less tendency to cause brain stem compression.
Dementia pugilistica (DP) is associated with chronic traumatic brain injury (CTBI), and leads to a “punch drunk” syndrome characterized by impairments in memory and executive function, behavioral changes, and motor signs. Microscopic features include the accumulation of neurofibrillary tangles (NFTs), beta-amyloid (Aβ), and TAR DNA binding protein 43 (TDP-43) pathology. Here we describe detailed clinical and neuropathological data about a 55-year-old retired boxer (ApoE3/4), who presented with executive dysfunction and behavioral impairments. At autopsy, significant Aβ pathology was seen, primarily in the form of diffuse plaques. Tau pathology was extensive and was determined to be of Braak and Braak stage VI. Frontal white matter showed evidence of glial tau inclusions (astrocytes and oligodendroglia). Cerebrovascular pathology was minimal with patchy amyloid angiopathy. Inflammation was another key feature, including microglial activation and significant C1q labeling of neurons, along with NFTs. TDP-43-positive pathology was also observed. Inflammation may be a key inciting as well as propagating feature of DP neuropathology.
beta-amyloid; C1q; chronic traumatic encephalopathy; tauopathy; TDP-43
This paper presents the first comprehensive effort to provide an overview of the research associated with the World Health Organization (WHO) headquarters in 2006/07.
Information was obtained by questionnaire and interviews with senior staff operating at WHO headquarters in Geneva. Research type, purpose and resources (both financial and staff) were defined and compared for each of the 37 departments identified and a comparative analysis was made with the global burden of disease as expressed by Disability Adjusted Life Years (DALY).
Research expenditure in 2006/07 was estimated at US$215 million. WHO is involved in more than 60 research networks/partnerships and often WHO itself is the network host.
Using the DALY model, 84% of the funding WHO allocates to research goes to DALY Type I diseases (communicable, maternal, perinatal and nutritional diseases) which represents 40% of DALY. 4% is allocated to Daly Type II (non-communicable diseases) which contributes to 48% of DALY.
45% of WHO permanent staff are involved with health research and the WHO's approach to research is predominantly focused on policy, advocacy, health systems and population based research. The Organization principally undertakes secondary research using published data and commissions others to conduct this work through contracts or research grants. This approach is broadly in line with the stated strategy of the Organization.
The difficulty in undertaking this survey highlights the complexity of obtaining an Organization-wide assessment of research activity in the absence of common standards for research classification, methods for priority setting and a mechanism across WHO, or within the governance of global health research more generally, for managing a research portfolio.
This paper presents a strategic birds-eye view of the WHO research portfolio using methodologies that, with further development, may provide the strategic information required if there is to be balancing of research efforts between communicable disease, non-communicable disease and other pressing public health needs. As the rollout of the WHO strategy on research for health proceeds we would hope to see similar exercises undertaken at the WHO Regional Offices and in support of capacity building of national health research systems within Member States.
Objectives: To explore relationships between scuba diving activity, brain, and behaviour, and more specifically between global cerebral blood flow (CBF) or cognitive performance and total, annual, or last 6 months' frequencies, for standard dives or dives performed below 40 m, in cold water or warm sea geographical environments.
Methods: A prospective cohort study was used to examine divers from diving clubs around Lac Léman and Geneva University Hospital. The subjects were 215 healthy recreational divers (diving with self-contained underwater breathing apparatus). Main outcome measures were: measurement of global CBF by 133Xe SPECT (single photon emission computed tomography); psychometric and neuropsychological tests to assess perceptual-motor abilities, spatial discrimination, attentional resources, executive functioning, and memory; evaluation of scuba diving activity by questionnaire focusing on number and maximum depth of dives and geographical site of the diving activity (cold water v warm water); and body composition analyses (BMI).
Results: (1) A negative influence of depth of dives on CBF and its combined effect with BMI and age was found. (2) A specific diving environment (more than 80% of dives in lakes) had a negative effect on CBF. (3) Depth and number of dives had a negative influence on cognitive performance (speed, flexibility and inhibition processing in attentional tasks). (4) A negative effect of a specific diving environment on cognitive performance (flexibility and inhibition components) was found.
Conclusions: Scuba diving may have long-term negative neurofunctional effects when performed in extreme conditions, namely cold water, with more than 100 dives per year, and maximal depth below 40 m.
Medical and nursing staff are busy people and their turnover in a teaching hospital is high. Teaching them the use of a computer station in a variety of applications belonging to a Medical Information System has to be very short and efficient. Data collection and retrieval has to be simple and accurate. Users training and permanent support may be an overwhelming task in a large hospital because of the numerous employees, the numerous medical departments, and long distances between groups of terminals running the same application. The tree branching logic of a frame selection system and a specially designed video-telephone station have been implemented at the University Hospital of Geneva as key elements actually reducing nurses and doctors initial training to a minimum. Numerical data are presented on the number of users, their training periods, and their activity on terminals.
Vascular cognitive impairment is an umbrella term for cognitive dysfunction associated with and presumed to be caused by vascular brain damage. Autopsy studies have identified microinfarcts as an important neuropathological correlate of vascular cognitive impairment that escapes detection by conventional magnetic resonance imaging (MRI). As a frame of reference for future high-resolution MRI studies, we systematically reviewed the literature on neuropathological studies on cerebral microinfarcts in the context of vascular disease, vascular risk factors, cognitive decline and dementia. We identified 32 original patient studies involving 10,515 people. The overall picture is that microinfarcts are common, particularly in patients with vascular dementia (weighted average 62%), Alzheimer's disease (43%), and demented patients with both Alzheimer-type and cerebrovascular pathology (33%) compared with nondemented older individuals (24%). In many patients, multiple microinfarcts were detected. Microinfarcts are described as minute foci with neuronal loss, gliosis, pallor, or more cystic lesions. They are found in all brain regions, possibly more so in the cerebral cortex, particularly in watershed areas. Reported sizes vary from 50 μm to a few mm, which is within the detection limit of current high-resolution MRI. Detection of these lesions in vivo would have a high potential for future pathophysiological studies in vascular cognitive impairment.
cerebral microinfarct; cerebrovascular disease; dementia; MRI; neuropathology