Showing papers in "Alzheimers & Dementia in 2011"

The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease

Abstract: The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

Abstract: The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.

Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

Abstract: Background Criteria for the clinical diagnosis of Alzheimer's disease (AD) were established in 1984. A broad consensus now exists that these criteria should be revised to incorporate state-of-the-art scientific knowledge. Methods The National Institute on Aging (NIA) and the Alzheimer's Association sponsored a series of advisory round table meetings in 2009 whose purpose was to establish a process for revising diagnostic and research criteria for AD. The recommendation from these advisory meetings was that three separate work groups should be formed with each assigned the task of formulating diagnostic criteria for one phase of the disease: the dementia phase; the symptomatic, pre-dementia phase; and the asymptomatic, preclinical phase of AD. Results Two notable differences from the AD criteria published in 1984 are incorporation of biomarkers of the underlying disease state and formalization of different stages of disease in the diagnostic criteria. There was a broad consensus within all three workgroups that much additional work is needed to validate the application of biomarkers for diagnostic purposes. In the revised NIA-Alzheimer's Association criteria, a semantic and conceptual distinction is made between AD pathophysiological processes and clinically observable syndromes that result, whereas this distinction was blurred in the 1984 criteria. Conclusions The new criteria for AD are presented in three documents. The core clinical criteria of the recommendations regarding AD dementia and MCI due to AD are intended to guide diagnosis in the clinical setting. However, the recommendations of the preclinical AD workgroup are intended purely for research purposes.

Neuropsychiatric symptoms in Alzheimer’s disease

Abstract: Neuropsychiatric symptoms (NPS) are core features of Alzheimer's disease and related dementias. Once thought to emerge primarily in people with late-stage disease, these symptoms are currently known to manifest commonly in very early disease and in prodromal phases, such as mild cognitive impairment. Despite decades of research, reliable treatments for dementia-associated NPS have not been found, and those that are in widespread use present notable risks for people using these medications. An Alzheimer's Association Research Roundtable was convened in the spring of 2010 to review what is known about NPS in Alzheimer's disease, to discuss classification and underlying neuropathogenesis and vulnerabilities, and to formulate recommendations for new approaches to tailored therapeutics.

Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup.

Abstract: Amyloid imaging related abnormalities (ARIA) have now been reported in clinical trials with multiple therapeutic avenues to lower amyloid-b burden in Alzheimer’s disease (AD). In response to concerns raised by the Food and Drug Administration, the Alzheimer’s Association Research Roundtable convened a working group to review the publicly available trial data, attempts at developinganimalmodels,andtheliteratureonthenaturalhistoryandpathologyofrelatedconditions.The

Trends in the incidence and prevalence of Alzheimer’s disease, dementia, and cognitive impairment in the United States

Abstract: Declines in heart disease and stroke mortality rates are conventionally attributed to reductions in cigarette smoking, recognition and treatment of hypertension and diabetes, effective medications to improve serum lipid levels and to reduce clot formation, and general lifestyle improvements. Recent evidence implicates these and other cerebrovascular factors in the development of a substantial proportion of dementia cases. Analyses were undertaken to determine whether corresponding declines in age-specific prevalence and incidence rates for dementia and cognitive impairment have occurred in recent years. Data spanning 1 or 2 decades were examined from community-based epidemiological studies in Minnesota, Illinois, and Indiana, and from the Health and Retirement Study, which is a national survey. Although some decline was observed in the Minnesota cohort, no statistically significant trends were apparent in the community studies. A significant reduction in cognitive impairment measured by neuropsychological testing was identified in the national survey. Cautious optimism appears justified.

The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging and the Alzheimer's Association workgroup

Abstract: The National Institute on Aging and the Alzheimer’s Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer’s disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD

The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers

Abstract: Background The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer’s disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer’s Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.

National estimates of the prevalence of Alzheimer's disease in the United States*

Abstract: Several methods of estimating prevalence of dementia are presented in this article. For both Brookmeyer and the Chicago Health and Aging project (CHAP), the estimates of prevalence are derived statistically, forward calculating from incidence and survival figures. The choice of incidence rates on which to build the estimates may be critical. Brookmeyer used incidence rates from several published studies, whereas the CHAP investigators applied the incidence rates observed in their own cohort. The Aging, Demographics, and Memory Study (ADAMS) and the East Boston Senior Health Project (EBSHP) were sample surveys designed to ascertain the prevalence of Alzheimer’s disease and dementia. ADAMS obtained direct estimates by relying on probability sampling nationwide. EBSHP relied on projection of localized prevalence estimates to the national population. The sampling techniques of ADAMS and EBSHP were rather similar, whereas their disease definitions were not. By contrast, EBSPH and CHAP have similar disease definitions internally, but use different calculation techniques, and yet arrive at similar prevalence estimates, which are considerably greater than those obtained by either Brookmeyer or ADAMS. Choice of disease definition may play the larger role in explaining differences in observed prevalence between these studies. 2011 The Alzheimer’s Association. All rights reserved.

Executive function and instrumental activities of daily living in mild cognitive impairment and Alzheimer's disease

Abstract: Background Impairment in instrumental activities of daily living (IADL) leads to early loss in productivity and adds significant burden to caregivers. Executive dysfunction is thought to be an important contributor to functional impairment. The objective of this study was to investigate the relationship between executive function and IADL in a large cohort of well-characterized normal older controls, mild cognitive impairment (MCI), and patients with mild Alzheimer's disease, separately as well as across the entire sample, while accounting for demographic, cognitive, and behavioral factors. Methods Subjects with baseline clinical datasets (n = 793) from the Alzheimer's Disease Neuroimaging Initiative study (228 normal older controls, 387 MCI, 178 Alzheimer's disease) were included in the analysis. A multiple regression model was used to assess the relationship between executive function and IADL. Results A multiple regression model, including diagnosis, global cognitive impairment, memory performance, and other covariates demonstrated a significant relationship between executive dysfunction and IADL impairment across all subjects ( R 2 = .60, P s = −.044, P = .005; Trailmaking Test B–A, quadratic relation, P = .01). Similarly, an analysis using MCI subjects only yielded a significant relationship ( R 2 = .16, P s = −.08, P = .001). Conclusions These results suggest that executive dysfunction is a key contributor to impairment in IADL. This relationship was evident even after accounting for degree of memory deficit across the continuum of cognitive impairment and dementia.

Extended results of the Alzheimer's disease anti-inflammatory prevention trial.

Abstract: Background Epidemiologic evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer's dementia (AD), but randomized trials show no benefit from NSAIDs in patients with symptomatic AD. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) randomized 2528 elderly persons to naproxen or celecoxib versus placebo for 2 years (standard deviation=11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups. Methods We continued the double-masked ADAPT protocol for 2 additional years to investigate incidence of AD (primary outcome). We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Aβ 1-42. Results Including 40 new events observed during follow-up of 2071 randomized individuals (92% of participants at treatment cessation), there were 72 AD cases. Overall, NSAID-related harm was no longer evident, but secondary analyses showed that increased risk remained notable in the first 2.5 years of observations, especially in 54 persons enrolled with cognitive impairment––no dementia (CIND). These same analyses showed later reduction in AD incidence among asymptomatic enrollees who were given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration. Conclusions These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, as follows: NSAIDs have an adverse effect in later stages of AD pathogenesis, whereas asymptomatic individuals treated with conventional NSAIDs such as naproxen experience reduced AD incidence, but only after 2 to 3 years. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies.

Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease

Abstract: Background The promise of Alzheimer’s disease biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging measure in Alzheimer’s disease and thus represents the most rational target for an initial effort at standardization. Methods and Results The authors of this position paper propose a path toward this goal. The steps include the following: (1) Establish and empower an oversight board to manage and assess the effort, (2) adopt the standardized definition of anatomic hippocampal boundaries on magnetic resonance imaging arising from the European Alzheimer’s Disease Centers–Alzheimer’s Disease Neuroimaging Initiative hippocampal harmonization effort as a reference standard, (3) establish a scientifically appropriate, publicly available reference standard data set based on manual delineation of the hippocampus in an appropriate sample of subjects (Alzheimer’s Disease Neuroimaging Initiative), and (4) define minimum technical and prognostic performance metrics for validation of new measurement techniques using the reference standard data set as a benchmark. Conclusions Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent was to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry was envisioned as a template that could be applied to other imaging biomarkers.

Circadian activity rhythms and risk of incident dementia and mild cognitive impairment in older women

Abstract: tients, prevalence rate: 3.7%), 5.1% an AD with depressive mood and 14.9% a mixed AD. Prevalence rate of ADWAwas 4.8% and 3.5% among the patients included respectively by psychiatrists or GPs(p 1⁄4 0.13). The main life stressor events involved in ADWA development were: serious personal illness or health problem (29.4%), illness of a familymember (20.6%), familial conflict (12.5%), problems with children (as child leaving the family, divorce.)(7.4%), and work-related problems (7.4%). On Sheehan disability scale, at least moderate discomfort was observed in 82% of patients and a severe discomfort in 48.2%. Conclusions: The ADWA is frequent in aged patients with a prevalence rate of 3.7%. This underlines the importance of the phenomenology and suggests to study the link between anxiety and possible occurrence of dementia.

Metabolomic changes in autopsy-confirmed Alzheimer's disease

Abstract: Background Metabolomics, the global science of biochemistry, provides powerful tools to map perturbations in the metabolic network and enables simultaneous quantification of several metabolites to identify metabolic perturbances that might provide insights into disease. Methods In this pilot study, we took a targeted electrochemistry-based metabolomics approach where liquid chromatography followed by coulometric array detection enables quantification of over 30 metabolites within key neurotransmitter pathways (dopamine and serotonin) and pathways involved in oxidative stress. Results Using samples from postmortem ventricular cerebrospinal fluid (15 Alzheimer's disease [AD] and 15 nondemented subjects with autopsy-confirmed diagnoses) and by using regression models, correlations, Wilcoxon rank-sum tests, and t -tests we identified alterations in tyrosine, tryptophan, purine, and tocopherol pathways in patients with AD. Reductions in norepinephrine and its related metabolites were also seen, consistent with previously published data. Conclusions These data support further investigation of metabolomics in larger samples of clinical AD as well as in those with preclinical disease for use as biomarkers.

Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline

Abstract: Objective: Our aim was to test the association of vascular risk factor exposure in midlife with progression of MRI markers of brain aging and measures of cognitive decline. Methods: A total of 1,352 participants without dementia from the prospective Framingham Offspring Cohort Study were examined. Multivariable linear and logistic regressions were implemented to study the association of midlife vascular risk factor exposure with longitudinal change in white matter hyperintensity volume (WMHV), total brain volume (TBV), temporal horn volume, logical memory delayed recall, visual reproductions delayed-recall (VR-d), and Trail-Making Test B-A (TrB-A) performance a decade later. Results: Hypertension in midlife was associated with accelerated WMHV progression ( p p = 0.012). Midlife diabetes and smoking were associated with a more rapid increase in temporal horn volume, a surrogate marker of accelerated hippocampal atrophy ( p = 0.017 and p = 0.008, respectively). Midlife smoking also predicted a more marked decrease in total brain volume ( p = 0.025) and increased risk of extensive change in WMHV (odds ratio = 1.58 [95%confidence interval 1.07–2.33], p = 0.021). Obesity in midlife was associated with an increased risk of being in the top quartile of change in executive function (1.39 [1.02–1.88], p = 0.035) and increasing waist-to-hip ratio was associated with marked decline in TBV (10.81 [1.44–81.01], p = 0.021). Longitudinal changes in brain structure were significantly correlated with decline in memory and executive function. Conclusions: Midlife hypertension, diabetes, smoking, and obesity were associated with an increased rate of progression of vascular brain injury, global and hippocampal atrophy, and decline in executive function a decade later.

Biomarkers in Alzheimer's disease drug development

Abstract: Developing new therapies for Alzheimer's disease (AD) is critically important to avoid the impending public health disaster imposed by this common disorder. Means must be found to prevent, delay the onset, or slow the progression of AD. These goals will be achieved by identifying disease-modifying therapies and testing them in clinical trials. Biomarkers play an increasingly important role in AD drug development. In preclinical testing, they assist in decisions to develop an agent. Biomarkers in phase I provide insights into toxic responses and drug metabolism and in Phase II proof-of-concept trials they facilitate go/no-go decisions and dose finding. Biomarkers can play a role in identifying presymptomatic patients or specific patient subgroups. They can provide evidence of target engagement before clinical changes can be expected. Brain imaging can serve as a primary outcome in Phase II trials and as a key secondary outcome in Phase III trials. Magnetic resonance imaging is currently best positioned for use in large multicenter clinical trials. Cerebrospinal fluid (CSF) measures of amyloid beta protein (Aβ), tau protein, and hyperphosphorylated tau (p-tau) protein are sensitive and specific to the diagnosis of AD and may serve as inclusion criteria and possibly as outcomes in clinical trials targeting relevant pathways. Plasma measures of Aβ are of limited diagnostic value but may provide important information as a measure of treatment response. A wide variety of measures of detectable products of cellular processes are being developed as possible biomarkers accessible in the cerebrospinal fluid and plasma or serum. Surrogate markers that can function as outcomes in pivotal trials and reliably predict clinical outcomes are needed to facilitate primary prevention trials of asymptomatic persons where clinical measures may be of limited value. Fit-for-purpose biomarkers are increasingly available to guide AD drug development decisions.

Frequency of Alzheimer’s disease pathology at autopsy in patients with clinical normal pressure hydrocephalus

Abstract: Background Normal pressure hydrocephalus (NPH) is considered to be potentially treatable with the placement of a cerebrospinal fluid (CSF) shunt However, the procedure has been reported to have variable success, particularly with respect to improving the cognitive impairment in NPH The presence of neurologic comorbidities, particularly Alzheimer's disease (AD), may contribute to shunt responsiveness Uncovering the extent to which AD and NPH co-occur has implications for diagnosis and treatment of NPH Autopsy studies of patients with NPH during their lifetime would elucidate the frequency of such comorbidities Methods A search of the Sun Health Research Institute Brain Donation Program database was conducted between January 1, 1997 and April 1, 2009 to identify all cases with neuropathologic evidence of dementia as well as those of clinically diagnosed NPH We reviewed the medical records and brain findings of each NPH case Results Of the 761 cases autopsied over the study interval, 563 were found to have neuropathologic evidence meeting criteria for a dementing illness Of 563 cases, AD was found exclusively in 313 (56%), and 94 suffered from secondary diagnosis of dementia Nine of 761 cases were identified with a clinical diagnosis of NPH, which were among the 563 cases with neuropathology of dementing illness at autopsy, representing 16% (9/563) of the cases On review of brain autopsy reports of these nine patients, eight (89%) were found to have AD and one (11%) had progressive supranuclear palsy Review of the medical records of the nine NPH cases revealed the following clinical comorbidities: five suffered from AD, one from Parkinson's Disease, one from mild cognitive impairment, and one from seizure disorder Conclusions Given the findings of the present study, we support the AD-NPH theory and posit that AD is a common pathologic comorbidity in the setting of NPH and may preclude cognitive improvement postshunt placement This may influence the selection of cases for shunting in the future

Predictors of costs of care in Alzheimer's disease: a multinational sample of 1222 patients.

Abstract: Background The costs of care for patients with Alzheimer's disease are correlated with key measures of disease severity. This relationship is important in the economic evaluation of new treatments and is used to translate treatment efficacy into effects on costs through economic modeling. We aimed to identify what measures of disease severity are the most important predictors of societal costs of care and whether their relationship differs across countries. Methods Interviews were conducted with 1222 patient and caregiver pairs residing in the community or in residential care settings in Spain, Sweden, United Kingdom, and the United States. Assessments included costs of care (Resource Utilization in Dementia) and key disease severity measures: cognitive function (Mini-Mental State Examination), ability to perform Activities of Daily Living (ADL-ability, Disability Assessment for Dementia [DAD]), and behavioral symptoms (Neuropsychiatry Inventory (NPI)-severity). Results ADL-ability was the most important predictor of societal costs of care of community-dwelling patients in all countries. A one-point decrease in DAD resulted in a 1.4% increase in costs of care in Spain, United Kingdom, and the United States on average, and a 2% increase in Sweden. This translated into a 45% increase from a standard deviation decrease in DAD on average. NPI-severity and Mini-Mental State Examination were also significant predictors but with lesser effect. Although mean costs of care differed across countries, the important predictors were the same. Conclusion ADL-ability is the most important predictor of societal costs of care in community dwellings irrespective of country and should therefore be central in the economic evaluation of Alzheimer's disease therapies.

Disease progression model for cognitive deterioration from Alzheimer's Disease Neuroimaging Initiative database

Abstract: Background A mathematical model was developed to describe the longitudinal response in Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) obtained from the Alzheimer's Disease Neuroimaging Initiative. Methods The model was fit to the longitudinal ADAS-cog scores from 817 patients. Risk factors (age, apolipoprotein ɛ4 [ APOE ɛ4] genotype, gender, family history of AD, years of education) and baseline severity were tested as covariates. Results Rate of disease progression increased with baseline severity. Age, APOE ɛ4 genotype, and gender were identified as potential covariates influencing disease progression. The rate of disease progression in patients with mild to moderate AD was estimated as approximately 5.5 points/yr. Conclusions A disease progression model adequately described the natural decline of ADAS-cog observed in Alzheimer's Disease Neuroimaging Initiative. Baseline severity is an important covariate to predict a curvilinear rate of disease progression in normal elderly, mild cognitive impairment, and AD patients. Age, APOE ɛ4 genotype, and gender also influence the rate of disease progression.

The effect of TOMM40 poly-T length on gray matter volume and cognition in middle-aged persons with APOE ε3/ε3 genotype.

Abstract: Objective Apolipoprotein E ( APOE ) genotypes are associated with variable risk of developing late-onset Alzheimer's disease (LOAD), with APOE epsilon 4 ( APOE ɛ4) having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the translocase of the outer mitochondrial membrane (TOMM40) gene, has been shown to influence age of onset in LOAD, with very long (VL) poly-T length associated with earlier disease onset, and short poly-T length associated with later onset. In this study, we tested the hypothesis that brain and cognitive changes suggestive of presymptomatic LOAD may be associated with this TOMM40 polymorphism. Methods Among healthy APOE ɛ3 homozygous adults (N = 117; mean age, 55 years), we compared those who were homozygous for VL/VL (n = 35) TOMM40 poly-T lengths (who were presumably at higher risk) with those homozygous for short (S/S; n=38) poly-T lengths, as well as those with heterozygous (S/VL; n=44) poly-T length polymorphisms, on measures of learning and memory and on structural brain imaging. Results The VL/VL group showed lower performance than the S/S TOMM40 group on primacy retrieval from a verbal list learning task, a finding which is also seen in early Alzheimer's disease. A dose-dependent increase in the VL TOMM40 polymorphism (from no VL alleles, to S/VL heterozygous, to VL/VL homozygous) was associated with decreasing gray matter volume in the ventral posterior cingulate and medial ventral precuneus, a region of the brain affected early in LOAD. Conclusions These findings among APOE ɛ3/ɛ3 late middle-aged adults suggest that a subgroup with VL TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes.

Predictors of suicide in patients with dementia

Abstract: Background Assessing predictors of suicide and means of completion in patients with dementia may aid the development of interventions to reduce risk of suicide among the growing population of individuals with dementia. Methods This national, retrospective, cohort study used data from the Department of Veterans Affairs (fiscal years 2001–2005). The sample included patients ≥60 years old diagnosed with dementia (N = 294,952), of which 241 committed suicide. Potential predictors of suicide were identified using logistic regression. Suicide methods are also reported. Results Increased risk of suicide was associated with white race (OR: 2.4, 95% CI: 1.2, 4.8), depression (OR: 2.0, 95% CI: 1.5, 2.9), a history of inpatient psychiatric hospitalizations (OR: 2.3, 95% CI: 1.5, 3.5), and prescription fills of antidepressants (OR: 2.1, 95% CI: 1.6, 2.8) or anxiolytics (OR: 2.0, 95% CI: 1.5, 2.7). Nursing home admission was associated with lower suicide risk (OR: 0.3, 95% CI: 0.1, 0.8). Severity of medical comorbidity did not affect risk of suicide. Sensitivity analysis indicated that the majority of suicides occurred in those who were newly diagnosed with dementia. Firearms were the most common method of suicide (73%) used. Conclusions Given the higher rate of suicide in those receiving treatment for psychiatric symptoms and the high proportion that died using firearms, closer monitoring and assessment of gun access may be an important part of initial treatment planning for older male patients with dementia, particularly those with symptoms of depression or anxiety.

Transcranial Doppler ultrasound blood flow velocity and pulsatility index as systemic indicators for Alzheimer’s disease

Abstract: Background Multiple lines of evidence suggest that cardiovascular co-morbidities hasten the onset of Alzheimer’s disease (AD) or accelerate its course. Methods To evaluate the utility of cerebral vascular physical function and/or condition parameters as potential systemic indicators of AD, transcranial Doppler (TCD) ultrasound was used to assess cerebral blood flow and vascular resistance of the 16 arterial segments comprising the circle of Willis and its major tributaries. Results Our study showed that decreased arterial mean flow velocity and increased pulsatility index are associated with a clinical diagnosis of presumptive AD. Cerebral blood flow impairment shown by these parameters reflects the global hemodynamic and structural consequences of a multifaceted disease process yielding diffuse congestive microvascular pathology, increased arterial rigidity, and decreased arterial compliance, combined with putative age-associated cardiovascular output declines. Conclusions TCD evaluation offers direct physical confirmation of brain perfusion impairment and might ultimately provide a convenient and a noninvasive means to assess the efficacy of medical interventions on cerebral blood flow or reveal incipient AD. In the near term, TCD-based direct assessments of brain perfusion might offer the prospect of preventing or mitigating AD simply by revealing patients who would benefit from interventions to improve circulatory system function.

Harmonization of magnetic resonance-based manual hippocampal segmentation: a mandatory step for wide clinical use.

Abstract: Hippocampal atrophy is a marker of disease state and progression in Alzheimer's disease. The gold standard to measure hippocampal volume is through manual segmentation. A number of protocols to measure hippocampal volume through manual segmentation have been developed, but the marked heterogeneity of anatomical landmarks has given rise to wide variability of volume estimates. With the aim of fostering the use of hippocampal volume in routine clinical settings, an international task force is currently working on developing a harmonized protocol that will resolve and reduce the present heterogeneity. The task force will then validate the harmonized protocol, develop harmonized probabilistic hippocampal maps, and develop illustrative and educational material on the use of the harmonized protocol and maps.

The measurement of everyday cognition: development and validation of a short form of the Everyday Cognition scales.

Abstract: Background This study describes the development and validation of a shortened version of the Everyday Cognition (ECog) scales [Tomaszewski Farias et al. Neuropsychology 2008;22:531–44], an informant-rated questionnaire designed to detect cognitive and functional decline. Methods External, convergent, and divergent validities and internal consistency were examined. Data were derived from informant ratings of 907 participants who were either cognitively normal, had mild cognitive impairment (MCI), or had dementia. Results Twelve items were included in the shortened version (ECog-12). The ECog-12 strongly correlated with established functional measures and neuropsychological scores, only weakly with age and education, and demonstrated high internal consistency. The ECog-12 showed excellent discrimination between the dementia and normal groups (area under the receiver operator characteristic curve=0.95, CI=0.94–0.97), and showed promise in discriminating normal older adults from those with any cognitive impairment (i.e., MCI or dementia). Discrimination between the MCI and normal groups was poor. Conclusions The ECog-12 shows promise as a clinical tool for assisting clinicians in identifying individuals with dementia.

Stabilization of neurotoxic Alzheimer amyloid-beta oligomers by protein engineering

Abstract: Soluble oligomeric aggregates of the amyloid-β peptide (Aβ) have been implicated in the pathogenesis of Alzheimer’s disease (AD). Although the conformation adopted by Aβ within these aggregates is not known, a β-hairpin conformation is known to be accessible to monomeric Aβ. Here we show that this β-hairpin is a building block of toxic Aβ oligomers by engineering a doublecysteine mutant (called AβCC) in which the β-hairpin is stabilized by an intramolecular disulfide bond. Aβ40CC and Aβ42CC both spontaneously form stable oligomeric species with distinct molecular weights and secondary-structure content, but both are unable to convert into amyloid fibrils. Biochemical and biophysical experiments and assays with conformation-specific antibodies used to detect Aβ aggregates in vivo indicate that the wild-type oligomer structure is preserved and stabilized in AβCC oligomers. Stable oligomers are expected to become highly toxic and, accordingly, we find that β-sheet-containing Aβ42CC oligomers or protofibrillar species formed by these oligomers are 50 times more potent inducers of neuronal apoptosis than amyloid fibrils or samples of monomeric wild-type Aβ42, in which toxic aggregates are only transiently formed. The possibility of obtaining completely stable and physiologically relevant neurotoxic Aβ oligomer preparations will facilitate studies of their structure and role in the pathogenesis of AD. For example, here we show how kinetic partitioning into different aggregation pathways can explain why Aβ42 is more toxic than the shorter Aβ40, and why certain inherited mutations are linked to protofibril formation and early-onset AD.

Assessment of cognition in mild cognitive impairment: A comparative study

Abstract: The demand for rapidly administered, sensitive, and reliable cognitive assessments that are specifically designed for identifying individuals in the earliest stages of cognitive decline (and to measure subtle change over time) has escalated as the emphasis in Alzheimer’s disease clinical research has shifted from clinical diagnosis and treatment toward the goal of developing presymptomatic neuroprotective therapies. To meet these changing clinical requirements, cognitive measures or tailored batteries of tests must be validated and determined to be fit-for-use for the discrimination between cognitively healthy individuals and persons who are experiencing very subtle cognitive changes that likely signal the emergence of early mild cognitive impairment. We sought to collect and review data systematically from a wide variety of (mostly computer-administered) cognitive measures, all of which are currently marketed or distributed with the claims that these instruments are sensitive and reliable for the early identification of disease or, if untested for this purpose, are promising tools based on other variables. The survey responses for 16 measures/batteries are presented in brief in this review; full survey responses and summary tables are archived and publicly available on the Campaign to Prevent Alzheimer’s Disease by 2020 Web site (http://pad2020.org). A decision tree diagram highlighting critical decision points for selecting measures to meet varying clinical trials requirements has also been provided. Ultimately, the survey questionnaire, framework, and decision guidelines provided in this review should remain as useful aids for the evaluation of any new or updated sets of instruments in the years to come.

Operationalizing diagnostic criteria for Alzheimer’s disease and other age-related cognitive impairment—Part 2

Abstract: This article focuses on the effects of operational differences in case ascertainment on estimates of prevalence and incidence of cognitive impairment and/or dementia of the Alzheimer type. Experience and insights are discussed by investigators from the Framingham Heart Study, the East Boston Senior Health Project, the Chicago Health and Aging Project, the Mayo Clinic Study of Aging, the Baltimore Longitudinal Study of Aging, and the Aging, Demographics, and Memory Study. There is a general consensus that the single most important factor determining prevalence estimates of Alzheimer's disease (AD) is the severity of cognitive impairment used as a threshold to define cases. Studies that require a level of cognitive impairment in which persons are unable to provide self-care will have much lower estimates than the studies aimed at identifying persons in the earliest stages of AD. There are limited autopsy data from the aforementioned epidemiological studies to address accuracy in the diagnosis of etiological subtype, namely the specification of AD alone or in combination with other types of pathology. However, other community-based cohort studies show that many persons with mild cognitive impairment and also some persons without dementia or mild cognitive impairment meet pathological criteria for AD, thereby suggesting that the number of persons who would benefit from an effective secondary prevention intervention is probably higher than the published prevalence estimates. Improved accuracy in the clinical diagnosis of AD is anticipated with the addition of molecular and structural biomarkers in the next generation of epidemiological studies.

Serum homocysteine and dementia: Meta-analysis of eight cohort studies including 8669 participants

Abstract: Background Prospective cohort studies have not been consistent in showing an association between serum homocysteine and dementia. Objective To conduct a meta-analysis of cohort studies that examined the relationship between serum homocysteine and dementia, and to estimate the change in risk of dementia for a unit change in serum homocysteine. Methods The data from eight cohort studies (involving 8669 participants; range of mean ages, 47–81 years; median duration of study, 5 years) of serum homocysteine on the incidence of dementia were combined and the odds ratio of dementia per 5 μmol/L increase in serum homocysteine was determined. Results There was a statistically significant association between serum homocysteine and the incidence of dementia: the odds ratio for a 5 μmol/L increase in serum homocysteine was 1.35 (95% confidence interval, 1.02–1.79) or 1.50 (1.13–2.00) adjusted for regression dilution bias. The odds ratio for a 3 μmol/L decrease in serum homocysteine (the average reduction expected using folic acid and B12) was 0.78 (0.66–0.93). Conclusion The meta-analysis of epidemiological cohort studies shows a positive association between serum homocysteine and dementia. Although the results do not provide evidence of cause and effect, they do provide an estimate of the expected effect if the relationship were causal; an approximate 20% reduction in risk of dementia from treatment with folic acid and B12.

Assessment of cognition in early dementia

Abstract: Better tools for assessing cognitive impairment in the early stages of Alzheimer's disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer's Association convened a meeting to discuss state of the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real-world situations in order to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.