Showing papers on "Cognitive decline published in 2012"

A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline

Abstract: The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.

Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline

Abstract: While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE e4 status. Levels of IRS-1 pS⁶¹⁶ and IRS-1 pS⁶³⁶/⁶³⁹ and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE e4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.

The ageing cortical synapse: hallmarks and implications for cognitive decline

Abstract: Normal ageing is associated with impairments in cognitive function, including memory. These impairments are linked, not to a loss of neurons in the forebrain, but to specific and relatively subtle synaptic alterations in the hippocampus and prefrontal cortex. Here, we review studies that have shed light on the cellular and synaptic changes observed in these brain structures during ageing that can be directly related to cognitive decline in young and aged animals. We also discuss the influence of the hormonal status on these age-related alterations and recent progress in the development of therapeutic strategies to limit the impact of ageing on memory and cognition in humans.

Cognitive stimulation to improve cognitive functioning in people with dementia

Abstract: Background Cognitive stimulation is an intervention for people with dementia which offers a range of enjoyable activities providing general stimulation for thinking, concentration and memory usually in a social setting, such as a small group. Its roots can be traced back to Reality Orientation (RO), which was developed in the late 1950s as a response to confusion and disorientation in older patients in hospital units in the USA. RO emphasised the engagement of nursing assistants in a hopeful, therapeutic process but became associated with a rigid, confrontational approach to people with dementia, leading to its use becoming less and less common. Cognitive stimulation is often discussed in normal ageing as well as in dementia. This reflects a general view that lack of cognitive activity hastens cognitive decline. With people with dementia, cognitive stimulation attempts to make use of the positive aspects of RO whilst ensuring that the stimulation is implemented in a sensitive, respectful and person-centred manner. There is often little consistency in the application and availability of psychological therapies in dementia services, so a systematic review of the available evidence regarding cognitive stimulation is important in order to identify its effectiveness and to place practice recommendations on a sound evidence base. Objectives To evaluate the effectiveness and impact of cognitive stimulation interventions aimed at improving cognition for people with dementia, including any negative effects. Search methods The trials were identified from a search of the Cochrane Dementia and Cognitive Improvement Group Specialized Register, called ALOIS (updated 6 December 2011). The search termsused were: cognitive stimulation, reality orientation, memory therapy, memory groups, memory support, memory stimulation, global stimulation, cognitive psychostimulation. Supplementary searches were performed in a number of major healthcare databases and trial registers to ensure that the search was up to date and comprehensive. Selection criteria All randomised controlled trials (RCTs) of cognitive stimulation for dementia which incorporated a measure of cognitive change were included. Data collection and analysis Data were extracted independently by two review authors using a previously tested data extraction form. Study authors were contacted for data not provided in the papers. Two review authors conducted independent assessments of the risk of bias in included studies. Main results Fifteen RCTs were included in the review. Six of these had been included in the previous review of RO. The studies included participants from a variety of settings, interventions that were of varying duration and intensity, and were from several different countries. The quality of the studies was generally low by current standards but most had taken steps to ensure assessors were blind to treatment allocation. Data were entered in the meta-analyses for 718 participants (407 receiving cognitive stimulation, 311 in control groups). The primary analysis was on changes that were evident immediately at the end of the treatment period. A few studies provided data allowing evaluation of whether any effects were subsequently maintained. A clear, consistent benefit on cognitive function was associated with cognitive stimulation (standardised mean difference (SMD) 0.41, 95% CI 0.25 to 0.57). This remained evident at follow-up one to three months after the end of treatment. In secondary analyses with smaller total sample sizes, benefits were also noted on self-reported quality of life and well-being (standardised mean difference: 0.38 [95% CI: 0.11, 0.65]); and on staff ratings of communication and social interaction (SMD 0.44, 95% CI 0.17 to 0.71). No differences in relation to mood (self-report or staff-rated), activities of daily living, general behavioural function or problem behaviour were noted. In the few studies reporting family caregiver outcomes, no differences were noted. Importantly, there was no indication of increased strain on family caregivers in the one study where they were trained to deliver the intervention. Authors' conclusions There was consistent evidence from multiple trials that cognitive stimulation programmes benefit cognition in people with mild to moderate dementia over and above any medication effects. However, the trials were of variable quality with small sample sizes and only limited details of the randomisation method were apparent in a number of the trials. Other outcomes need more exploration but improvements in self-reported quality of life and well-being were promising. Further research should look into the potential benefits of longer term cognitive stimulation programmes and their clinical significance.

An epigenetic blockade of cognitive functions in the neurodegenerating brain

Abstract: Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer's disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer's-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer's disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.

Timing of Onset of Cognitive Decline: Results from Whitehall II Prospective Cohort Study

Abstract: OBJECTIVES: To estimate 10 year decline in cognitive function from longitudinal data in a middle aged cohort and to examine whether age cohorts can be compared with cross sectional data to infer the effect of age on cognitive decline. DESIGN: Prospective cohort study. At study inception in 1985-8, there were 10,308 participants, representing a recruitment rate of 73%. SETTING: Civil service departments in London, United Kingdom. PARTICIPANTS: 5198 men and 2192 women, aged 45-70 at the beginning of cognitive testing in 1997-9. MAIN OUTCOME MEASURE: Tests of memory, reasoning, vocabulary, and phonemic and semantic fluency, assessed three times over 10 years. RESULTS: All cognitive scores, except vocabulary, declined in all five age categories (age 45-49, 50-54, 55-59, 60-64, and 65-70 at baseline), with evidence of faster decline in older people. In men, the 10 year decline, shown as change/range of test × 100, in reasoning was -3.6% (95% confidence interval -4.1% to -3.0%) in those aged 45-49 at baseline and -9.6% (-10.6% to -8.6%) in those aged 65-70. In women, the corresponding decline was -3.6% (-4.6% to -2.7%) and -7.4% (-9.1% to -5.7%). Comparisons of longitudinal and cross sectional effects of age suggest that the latter overestimate decline in women because of cohort differences in education. For example, in women aged 45-49 the longitudinal analysis showed reasoning to have declined by -3.6% (-4.5% to -2.8%) but the cross sectional effects suggested a decline of -11.4% (-14.0% to -8.9%). CONCLUSIONS: Cognitive decline is already evident in middle age (age 45-49).

Amyloid deposition, hypometabolism, and longitudinal cognitive decline.

Abstract: The emergence of positron emission tomography (PET) for imaging fibrillar β-amyloid (Aβ) in vivo is a critical development in the study of Alzheimer disease (AD). Recent amyloid PET studies have raised important questions about how amyloid deposition influences cognitive trajectories, particularly early in the course of disease. Determining the consequences of Aβ at different phases of disease and the relationship between Aβ and other well-known biomarkers of AD such as 18F-fluorodeoxyglucose (FDG) remain important questions that will contribute to our understanding of the clinical relevance of amyloid PET imaging and the development of effective therapies for AD. Hypometabolism, measured with FDG-PET, is associated with cognitive decline1 and conversion from mild cognitive impairment (MCI) to AD.2,3 Recent work has demonstrated that the presence of amyloid is also associated with decline4,5 and conversion.6,7 Integrating data from a variety of sources, researchers have proposed that the time course of Aβ deposition and hypometabolism depends on disease stage,8–10 such that amyloid deposition precedes synaptic and neuronal dysfunction, which is in turn followed by cognitive decline. This model has been supported by several studies comparing the 2 PET measurements with respect to longitudinal decline,11,12 but this work has been limited by small sample sizes and access to patients at different phases of disease. In this study, FDG-PET and amyloid PET data acquired through the Alzheimer’s Disease Neuroimaging Initiative (ADNI) made it possible to compare these measurements in a large sample at different levels of disease severity. [18F]Florbetapir is a PET ligand that has been recently added to the ADNI imaging protocol, and has been validated in a study demonstrating close correspondence between cortical amyloid deposition measured with florbetapir in end-of-life patients and immunohistochemistry measurements of fibrillar Aβ at autopsy.13 We examined cross-sectional relationships between Aβ (measured with florbetapir), hypometabolism (measured with FDG-PET), and cognitive performance (measured with the cognitive subscale of the Alzheimer’s Disease Assessment Scale [ADAS-cog]) in the ADNI population. A subset of the normal and MCI participants had retrospective longitudinal cognitive performance data available. Examining PET measurements (florbetapir, FDG) and cognitive change over time in these 2 diagnostic groups (normal, MCI) allowed us to test the hypothesis that amyloid deposition precedes hypometabolism and both are linked to longitudinal decline.

Total daily physical activity and the risk of AD and cognitive decline in older adults

Abstract: Objective: Studies examining the link between objective measures of total daily physical activity and incident Alzheimer disease (AD) are lacking. We tested the hypothesis that an objective measure of total daily physical activity predicts incident AD and cognitive decline. Methods: Total daily exercise and nonexercise physical activity was measured continuously for up to 10 days with actigraphy (Actical®; Philips Healthcare, Bend, OR) from 716 older individuals without dementia participating in the Rush Memory and Aging Project, a prospective, observational cohort study. All participants underwent structured annual clinical examination including a battery of 19 cognitive tests. Results: During an average follow-up of about 4 years, 71 subjects developed clinical AD. In a Cox proportional hazards model adjusting for age, sex, and education, total daily physical activity was associated with incident AD (hazard ratio = 0.477; 95% confidence interval 0.273–0.832). The association remained after adjusting for self-report physical, social, and cognitive activities, as well as current level of motor function, depressive symptoms, chronic health conditions, and APOE allele status. In a linear mixed-effect model, the level of total daily physical activity was associated with the rate of global cognitive decline (estimate 0.033, SE 0.012, p = 0.007). Conclusions: A higher level of total daily physical activity is associated with a reduced risk of AD.

Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model

Abstract: In light of the rising prevalence of Alzheimer’s disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-β–induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD.

Aging and functional brain networks

Abstract: Aging is associated with changes in human brain anatomy and function and cognitive decline. Recent studies suggest the aging decline of major functional connectivity hubs in the 'default-mode' network (DMN). Aging effects on other networks, however, are largely unknown. We hypothesized that aging would be associated with a decline of short- and long-range functional connectivity density (FCD) hubs in the DMN. To test this hypothesis, we evaluated resting-state data sets corresponding to 913 healthy subjects from a public magnetic resonance imaging database using functional connectivity density mapping (FCDM), a voxelwise and data-driven approach, together with parallel computing. Aging was associated with pronounced long-range FCD decreases in DMN and dorsal attention network (DAN) and with increases in somatosensory and subcortical networks. Aging effects in these networks were stronger for long-range than for short-range FCD and were also detected at the level of the main functional hubs. Females had higher short- and long-range FCD in DMN and lower FCD in the somatosensory network than males, but the gender by age interaction effects were not significant for any of the networks or hubs. These findings suggest that long-range connections may be more vulnerable to aging effects than short-range connections and that, in addition to the DMN, the DAN is also sensitive to aging effects, which could underlie the deterioration of attention processes that occurs with aging.

The Neuropsychological Profile of Alzheimer Disease

Abstract: Neuropsychological assessment has featured prominently over the past 30 years in the characterization of dementia associated with Alzheimer disease (AD). Clinical neuropsychological methods have identified the earliest, most definitive cognitive and behavioral symptoms of illness, contributing to the identification, staging, and tracking of disease. With increasing public awareness of dementia, disease detection has moved to earlier stages of illness, at a time when deficits are both behaviorally and pathologically selective. For reasons that are not well understood, early AD pathology frequently targets large-scale neuroanatomical networks for episodic memory before other networks that subserve language, attention, executive functions, and visuospatial abilities. This chapter reviews the pathognomonic neuropsychological features of AD dementia and how these differ from "normal," age-related cognitive decline and from other neurodegenerative diseases that cause dementia, including cortical Lewy body disease, frontotemporal lobar degeneration, and cerebrovascular disease.

Exposure to particulate air pollution and cognitive decline in older women.

Abstract: Results: Higher levels of long-term exposure to both PM2.5-10 and PM2.5 were associated with significantly faster cognitive decline. Two-year decline on a global score was 0.020 (95% CI, �0.032 to �0.008) standard units worse per 10 µg/m 3 increment in PM2.5-10 exposure and 0.018 (95% CI, �0.035 to �0.002) units worse per 10 µg/m 3 increment in PM2.5 exposure. These differences in cognitive trajectory were similar to those between women in our cohort who were approximately 2 years apart in age, indicating that the effect of a 10-µg/m 3 increment in longterm PM exposure is cognitively equivalent to aging by approximately 2 years. Conclusion: Long-term exposure to PM2.5-10 and PM2.5 at levels typically experienced by many individuals in the United States is associated with significantly worse cognitive decline in older women.

Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study.

Abstract: Recent studies suggest that delirium is associated with risk of dementia and also acceleration of decline in existing dementia. However, previous studies may have been confounded by incomplete ascertainment of cognitive status at baseline. Herein, we used a true population sample to determine if delirium is a risk factor for incident dementia and cognitive decline. We also examined the effect of delirium at the pathological level by determining associations between dementia and neuropathological markers of dementia in patients with and without a history of delirium. The Vantaa 85+ study examined 553 individuals (92% of those eligible) aged ≥85 years at baseline, 3, 5, 8 and 10 years. Brain autopsy was performed in 52%. Fixed and random-effects regression models were used to assess associations between (i) delirium and incident dementia and (ii) decline in Mini-Mental State Examination scores in the whole group. The relationship between dementia and common neuropathological markers (Alzheimer-type, infarcts and Lewy-body) was modelled, stratified by history of delirium. Delirium increased the risk of incident dementia (odds ratio 8.7, 95% confidence interval 2.1-35). Delirium was also associated with worsening dementia severity (odds ratio 3.1, 95% confidence interval 1.5-6.3) as well as deterioration in global function score (odds ratio 2.8, 95% confidence interval 1.4-5.5). In the whole study population, delirium was associated with loss of 1.0 more Mini-Mental State Examination points per year (95% confidence interval 0.11-1.89) than those with no history of delirium. In individuals with dementia and no history of delirium (n = 232), all pathologies were significantly associated with dementia. However, in individuals with delirium and dementia (n = 58), no relationship between dementia and these markers was found. For example, higher Braak stage was associated with dementia when no history of delirium (odds ratio 2.0, 95% confidence interval 1.1-3.5, P = 0.02), but in those with a history of delirium, there was no significant relationship (odds ratio 1.2, 95% confidence interval 0.2-6.7, P = 0.85). This trend for odds ratios to be closer to unity in the delirium and dementia group was observed for neuritic amyloid, apolipoprotein e status, presence of infarcts, α-synucleinopathy and neuronal loss in substantia nigra. These findings are the first to demonstrate in a true population study that delirium is a strong risk factor for incident dementia and cognitive decline in the oldest-old. However, in this study, the relationship did not appear to be mediated by classical neuropathologies associated with dementia.

Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study

Abstract: Background This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer’s disease (AD).

Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial.

Abstract: †Background: Homocysteine is a risk factor for Alzheimer’s disease. In the first report on the VITACOG trial, we showed that homocysteine-lowering treatment with B vitamins slows the rate of brain atrophy in mild cognitive impairment (MCI). Here we report the effect of B vitamins on cognitive and clinical decline (secondary outcomes) in the same study. Methods:This was a double-blind, single-centre study, which included participants with MCI, aged ≥70y, randomly assigned to receive a daily dose of 0.8mg folic acid, 0.5mg vitamin B12 and 20mg vitamin B6 (133 participants) or placebo (133 participants) for 2y. Changes in cognitive or clinical function were analysed by generalized linear models or mixed-effects models. Results: The mean plasma total homocysteine was 30% lower in those treated with B vitamins relative to placebo. B vitamins stabilized executive function (CLOX) relative to placebo (P=0.015). There was significant benefit of B-vitamin treatment among participants with baseline homocysteine above the median (11.3mmol/L) in global cognition (Mini Mental State Examination, P<0.001), episodic memory (Hopkins Verbal Learning Test–delayed recall, P=0.001) and semantic memory (category fluency, P=0.037). Clinical benefit occurred in the B-vitamin group for those in the upper quartile of homocysteine at baseline in global clinical dementia rating score (P=0.02) and IQCODE score (P=0.01). Conclusion: In this small intervention trial, B vitamins appear to slow cognitive and clinical decline in peoplewithMCI,inparticularinthosewithelevatedhomocysteine.Furthertrialsareneededtoseeifthistreatment will slow or prevent conversion from MCI to dementia. Copyright # 2011 John Wiley & Sons, Ltd. Supporting information may be found in the online version of this article.

Cerebral microinfarcts: the invisible lesions

Abstract: Summary The association between small but still visible lacunar infarcts and cognitive decline has been established by population-based radiological and pathological studies. Microscopic examination of brain sections shows even smaller but substantially more numerous microinfarcts, the focus of this Review. These lesions often result from small vessel pathologies such as arteriolosclerosis or cerebral amyloid angiopathy. They typically go undetected in clinical–radiological correlation studies that rely on conventional structural MRI, although the largest acute microinfarcts can be detected by diffusion-weighted imaging. In view of their high numbers and widespread distribution, microinfarcts could directly disrupt important cognitive networks and thus account for some of the neurological dysfunction associated with lesions visible on conventional MRI such as lacunar infarcts and white matter hyperintensities. Standardised neuropathological assessment criteria and the development of non-invasive means of detection during life would be major steps towards understanding the causes and consequences of otherwise macroscopically invisible microinfarcts.

Accounting for bias due to selective attrition: The example of smoking and cognitive decline

Abstract: Background Selective attrition may introduce bias into analyses of the determinants of cognitive decline. This is a concern especially for risk factors, such as smoking, that strongly influence mortality and drop-out. Using inverse-probability-of-attrition weights (IPAWs), we examined the influence of selective attrition on the estimated association of current smoking (versus never smoking) with cognitive decline.

Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease–like pathology and cognitive decline

Abstract: The pathology of Alzheimer's disease has an inflammatory component that is characterized by upregulation of proinflammatory cytokines, particularly in response to amyloid-β (Aβ). Using the APPPS1 Alzheimer's disease mouse model, we found increased production of the common interleukin-12 (IL-12) and IL-23 subunit p40 by microglia. Genetic ablation of the IL-12/IL-23 signaling molecules p40, p35 or p19, in which deficiency of p40 or its receptor complex had the strongest effect, resulted in decreased cerebral amyloid load. Although deletion of IL-12/IL-23 signaling from the radiation-resistant glial compartment of the brain was most efficient in mitigating cerebral amyloidosis, peripheral administration of a neutralizing p40-specific antibody likewise resulted in a reduction of cerebral amyloid load in APPPS1 mice. Furthermore, intracerebroventricular delivery of antibodies to p40 significantly reduced the concentration of soluble Aβ species and reversed cognitive deficits in aged APPPS1 mice. The concentration of p40 was also increased in the cerebrospinal fluid of subjects with Alzheimer's disease, which suggests that inhibition of the IL-12/IL-23 pathway may attenuate Alzheimer's disease pathology and cognitive deficits.

Cardiovascular Risk Factors Promote Brain Hypoperfusion Leading to Cognitive Decline and Dementia

Abstract: Heart disease is the major leading cause of death and disability in the world. Mainly affecting the elderly population, heart disease and its main outcome, cardiovascular disease, have become an important risk factor in the development of cognitive decline and Alzheimer’s disease (AD). This paper examines the evidence linking chronic brain hypoperfusion induced by a variety of cardiovascular deficits in the development of cognitive impairment preceding AD. The evidence indicates a strong association between AD and cardiovascular risk factors, including ApoE4, atrial fibrillation, thrombotic events, hypertension, hypotension, heart failure, high serum markers of inflammation, coronary artery disease, low cardiac index, and valvular pathology. In elderly people whose cerebral perfusion is already diminished by their advanced age, additional reduction of cerebral blood flow stemming from abnormalities in the heart-brain vascular loop ostensibly increases the probability of developing AD. Evidence also suggests that a neuronal energy crisis brought on by relentless brain hypoperfusion may be responsible for protein synthesis abnormalities that later result in the classic neurodegenerative lesions involving the formation of amyloid-beta plaques and neurofibrillary tangles. Insight into how cardiovascular risk factors can induce progressive cognitive impairment offers an enhanced understanding of the multifactorial pathophysiology characterizing AD and ways at preventing or managing the cardiovascular precursors of this dementia.

Antioxidants for Alzheimer Disease: A Randomized Clinical Trial With Cerebrospinal Fluid Biomarker Measures

Abstract: Objective To evaluate whether antioxidant supplements presumed to target specific cellular compartments affected cerebrospinal fluid (CSF) biomarkers. Design Double-blind, placebo-controlled clinical trial. Setting Academic medical centers. Participants Subjects with mild to moderate Alzheimer disease. Intervention Random assignment to treatment for 16 weeks with 800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d of α-lipoic acid (E/C/ALA); 400 mg of coenzyme Q 3 times/d; or placebo. Main Outcome Measures Changes from baseline to 16 weeks in CSF biomarkers related to Alzheimer disease and oxidative stress, cognition (Mini-Mental State Examination), and function (Alzheimer's Disease Cooperative Study Activities of Daily Living Scale). Results Seventy-eight subjects were randomized; 66 provided serial CSF specimens adequate for biochemical analyses. Study drugs were well tolerated, but accelerated decline in Mini-Mental State Examination scores occurred in the E/C/ALA group, a potential safety concern. Changes in CSF Aβ42, tau, and P-tau 181 levels did not differ between the 3 groups. Cerebrospinal fluid F2-isoprostane levels, an oxidative stress biomarker, decreased on average by 19% from baseline to week 16 in the E/C/ALA group but were unchanged in the other groups. Conclusions Antioxidants did not influence CSF biomarkers related to amyloid or tau pathology. Lowering of CSF F2-isoprostane levels in the E/C/ALA group suggests reduction of oxidative stress in the brain. However, this treatment raised the caution of faster cognitive decline, which would need careful assessment if longer-term clinical trials are conducted. Trial Registration clinicaltrials.gov Identifier: NCT00117403

Total daily physical activity and the risk of AD and cognitive decline in older adultsAuthor Response

Abstract: Editors' Note: In reference to “Total daily physical activity and the risk of AD and cognitive decline in older adults” by Buchman et al., Dr. Abe points out that many subjects at the beginning of the study already had mild cognitive impairment, which could affect their activity level and likelihood of developing Alzheimer disease. He suggests that a longer observational period might have helped to compensate. The authors agree with Dr. Abe that an ideal study would only include subjects without cognitive impairment. Drs. Deisenhammer and Hegen lament that neutralizing antibodies against …

Developmental Influences on Adult Intelligence: The Seattle Longitudinal Study

Abstract: 1. Introduction and Preview 2. Methodological Issues 3. The Database 4. Cross-Sectional Studies 5. Longitudinal Studies 6. Studies of Cohort and Period Differences 7. Intervention Studies 8. Methodological Studies 9. The Relationship Between Cognitive Styles and Intellectual Functioning 10. Health and Maintenance of Intellectual Functioning 11. Health Behaviors and Intellectual Functioning 12. Lifestyle Variables That Affect Intellectual Functioning 13. The Sequential Study of Personality Traits and Attitudes 14. Influences of Personality on Cognition 15. Family Studies of Intellectual Abilities in Adulthood 16. Subjective Perceptions of Cognitive Change 17. Influences of Family Environment on Cognition 18. Biological Influences on Cognitive Change 19. The Prediction of Individual Cognitive Decline 20. The Role of Longitudinal Studies in the Early Detection of Dementia 21. Summary and Conclusions Appendix Tables References Index