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Objective: To study whether memory control beliefs predict response to memory training, or change as a result of participating in memory training. Methods: Eighty community based participants with ...

Background While an assessment of the right ventricular (RV) size remains challenging, the entire RV is can be imaged on coronary computed tomography angiography (CCTA) studies. With prospective ECG-triggering, the RV end diastolic volume (RVEDV) cannot be measured; however, the RV mid-diastolic volume (RVMDV) can still be measured accurately from routine CCTA data sets. The objective of this study is to establish normal reference values for RVMDV. Methods Right ventricular mid-diastolic volumes were measured in 4855 consecutive patients undergoing prospectively ECG-triggered coronary CTA. All patients with known cardiac or pulmonary disease (coronary artery disease, myocardial infarction, revascularization, heart failure, pulmonary hypertension, congenital heart disease, valvular heart disease, atrial fibrillation, implantable cardiac defibrillator implantation, cardiac transplant, or cardiac surgery) or smoking history (3313 patients) were excluded. Results 1542 patients were analyzed (mean age 56.4 ± 11.1 years, mean BSA 1.96 ± 0.26 and 47% male). The mean RVMDV for men and women was 168.6 ± 37.6 mL and 117.6 ± 26.4 mL, respectively. Mean BSA-indexed RVMDV was 80.0 ± 15.3 mL/m2 and 64.1 ± 12.2 mL/m2 for men and women, respectively. The presence of hypertension and diabetes did not have an impact on these values. RVMDV and BSA-indexed RVMDV were lower in women and in older individuals. Conclusion Normal reference ranges for RVMDV were established using prospectively ECG-triggered coronary CTA studies. This data can be used to identify patients with abnormal RV volumes and potentially RV dysfunction, adding incremental diagnostic value to routine CCTA studies.

Purpose: The impact of cardiology fellows (CFs) and interventional cardiology fellows (ICFs) on patient radiation and contrast exposure during diagnostic coronary angiography and percutaneous coronary intervention is unknown. Methods: Between 2011 and 2014, 16,175 cases were retrospectively assessed involving 27 CFs, 22 ICFs and 24 staff as primary operators. Results: During diagnostic coronary angiography, ICFs administered the lowest radiation dose (5,648±5,523 cGy*cm2; 1.30 ± 1.27 mSv)—achieving 22% less radiation than the staff (6,889±4,294 cGy*cm2; 1.58 ± 0.99 mSv) and 36% less than CFs (7,700±6,751 cGy*cm2; 1.77 ± 1.55 mSv) (p

OBJECTIVE: A rare variant in TREM2 (p.R47H, rs75932628) has been consistently reported to increase the risk for Alzheimer’s disease, while mixed evidence has been reported for association of the variant with other neurodegenerative diseases. Here, we investigated the frequency of the R47H variant in a diverse and well-characterized multicenter neurodegenerative disease cohort. METHODS: We examined the frequency of the R47H variant in a diverse neurodegenerative disease cohort, including a total of 3,058 patients clinically diagnosed with Alzheimer’s disease, frontotemporal dementia spectrum syndromes, mild cognitive impairment, progressive supranuclear palsy syndrome, corticobasal syndrome, or amyotrophic lateral sclerosis and 5,089 control subjects. RESULTS: We observed a significant association between the R47H variant and Alzheimer’s disease, while no association was observed with any other neurodegenerative disease included in this study. CONCLUSIONS: Our results support the consensus that the R47H variant is significantly associated with Alzheimer’s disease. However, we did not find evidence for association of the R47H variant with other neurodegenerative diseases.

Objectives:The goal of this study was to evaluate the ability of semantic (animal naming) and phonemic (FAS) fluency in their ability to discriminate between normal aging, amnestic-Mild Cognitive Impairment (a-MCI), and Alzheimer’s disease (AD).Design:We used binary logistic regressions, multinomial regressions, and discriminant analysis to evaluate the predictive value of semantic and phonemic fluency in regards to specific diagnostic classifications.Setting:Outpatient geriatric neuropsychology clinic.Participants:232 participants (normal aging = 99, a-MCI = 90, AD = 43; mean age = 65.75 years).Measurements:Mini-mental State Examination (MMSE), Controlled Oral Word Association TestResults:Results indicate that semantic and phonemic fluency were significant predictors of diagnostic classification, and semantic fluency explained a greater amount of the discriminant ability of the model.Conclusions:These results suggest that verbal fluency, particularly semantic fluency, may be an accurate and efficient tool in screening for early dementia in time-limited medical settings.

As the world's population ages and people live longer, the changes in the aging brain present substantial challenges to our health and society. With greater longevity come age-related diseases, many of which have direct and indirect influences on the health of the brain. Although there is some degree of predictable decline in brain functioning with aging, meaningful cognitive decline is not inevitable and is perhaps preventable. In this review, we present the case that the course of aging-related brain disease and dysfunction can be modified. We present the evidence for conditions and risk factors that may contribute to cognitive decline and dementia and for interventions that may mitigate their impact on cognitive functioning later in life, or even prevent them and their cognitive sequelae from developing. Although much work remains to be done to meet the challenges of the aging brain, strategies to promote its health have been demonstrated and offer much promise, which can only be realized if we mount a vigorous public health effort to implement these strategies.

Objective We sought to determine the prognostic value of coronary computed tomography angiography (CCTA) in patients with a history of percutaneous coronary intervention (PCI). Background Although the prognostic value of CCTA has been well studied, its incremental value in patients with previous PCI has not been robustly investigated. Methods Consecutive patients with previous PCI were prospectively enrolled and CCTA images were evaluated for coronary artery disease (CAD) severity. Patients were followed for major adverse cardiovascular events (MACE) which was a composite of cardiac death and non-fatal myocardial infarction. All-cause death was assessed as a secondary endpoint. Results A total of 501 patients were analyzed with a mean follow-up time of 59.5 ± 32.0 months and 52 patients (10.4%) experienced MACE. Multivariable Cox regression analysis showed that CAD severity was a predictor of MACE with 0, 1, 2, and 3 vessel disease having annual rates of 1.3%, 2.2%, 2.2%, and 5.3%, respectively. All-cause death was similar in all categories of CAD. Conclusions In patients with previous PCI, CAD severity as measured with CCTA has independent and incremental prognostic value.

Objectives:Geriatric depression often presents with memory and cognitive complaints that are associated with increased risk for Alzheimer’s disease (AD). In a parent clinical trial of escitalopram combined with memantine or placebo for geriatric depression and subjective memory complaints, we found that memantine improved executive function and delayed recall performance at 12 months (NCT01902004). In this report, we used positron emission tomography (PET) to assess the relationship between in-vivo amyloid and tau brain biomarkers and clinical and cognitive treatment response.Design:In a randomized double-blind placebo-controlled trial, we measured 2-(1-{6-[(2-[F18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile ([18F]FDDNP) binding at baseline and assessed mood and cognitive performance at baseline, posttreatment (6 months), and naturalistic follow-up (12 months).Participants:Twenty-two older adults with major depressive disorder and subjective memory complaints completed PET scans and were included in this report.Results:Across both treatment groups, higher frontal lobe [18F]FDDNP binding at baseline was associated with improvement in executive function at 6 months (corrected p = .045). This effect was no longer significant at 12 months (corrected p = .12). There was no association of regional [18F]FDDNP binding with change in mood symptoms (corrected p = .2).Conclusions:[18F]FDDNP binding may predict cognitive response to antidepressant treatment. Larger trials are required to further test the value of [18F]FDDNP binding as a biomarker for cognitive improvement with antidepressant treatment in geriatric depression.

Aims This large prospective cohort study sought to confirm the incremental prognostic value of coronary computed tomographic angiography (CCTA) measured over a prolonged follow-up duration. CCTA has diagnostic and prognostic value but data supporting its long-term prognostic value in a large prospectively recruited cohort with suspected coronary artery disease (CAD) has been limited. Methods and results Consecutive patients (without history of myocardial infarction, revascularization, cardiac transplantation, and congenital heart disease) were prospectively enrolled. CCTA was evaluated for CAD severity, total plaque score (TPS), and left ventricular ejection fraction. Patients were followed for major adverse events (MAE) and major adverse cardiac events (MACE). Over a total of 99 months, 8667 consecutive CCTA patients (mean age = 57.1 ± 11.1 years, 52.9% men) were prospectively enrolled and followed for a mean duration of 7.0 ± 2.6 years. At follow-up, there were a total of 723 MAE, 278 MACE, 547 all-cause deaths, 110 cardiac deaths, and 104 non-fatal myocardial infarction. Patients without coronary atherosclerosis at the time of CCTA had a very low annual event rate for both MAE and MACE (0.45%/year and 0.19%/year, respectively). Both MAE and MACE increased with increasing TPS and severity of CAD. In patients with non-obstructive CAD and who were statin-naive, TPS ≥5 had MACE rates >0.75%/year. Patients with high-risk CAD had an annual MAE and MACE rates of 3.52%/year and 2.58%/year, respectively. Adjusted hazard ratio of the severity of CAD based on multivariable analyses indicated that the prognostic values were incremental. Conclusion CCTA has independent and incremental prognostic value that is durable over time. The absence of coronary atherosclerosis portends an excellent prognosis. Patients with increasing non-obstructive plaque burden have worse prognosis and a TPS threshold ≥5 may identify a population that may benefit from statin therapy.

Author(s): Siddarth, Prabha; Rahi, Berna; Emerson, Natacha D; Burggren, Alison C; Miller, Karen J; Bookheimer, Susan; Lavretsky, Helen; Dobkin, Bruce; Small, Gary; Merrill, David A | Abstract: BackgroundPhysical activity (PA) plays a major role in maintaining cognition in older adults. PA has been shown to be correlated with total hippocampal volume, a memory-critical region within the medial temporal lobe (MTL). However, research on associations between PA and MTL sub-region integrity is limited.ObjectiveTo examine the relationship between PA, MTL thickness, and its sub-regions, and cognitive function in non-demented older adults with memory complaints.MethodsTwenty-nine subjects aged ≥60 years, with memory complaints were recruited for this cross-sectional study. PA was tracked for 7 days using accelerometers, and average number of steps/day determined. Subjects were categorized into two groups: those who walked ≤4000 steps/day (lower PA) and those with g4000 steps/day (higher PA). Subjects received neuropsychological testing and 3T MRI scans. Nonparametric ANCOVAs controlling for age examined differences between the two groups.ResultsTwenty-six subjects aged 72.7(8.1) years completed the study. The higher PA group (n = 13) had thicker fusiform gyrus (median difference = 0.11 mm, effect size (ES) = 1.43, p = 0.001) and parahippocampal cortex (median difference = 0.12 mm, ES = 0.93, p = 0.04) compared to the lower PA group. The higher PA group also exhibited superior performance in attention and information-processing speed (median difference = 0.90, ES = 1.61, p = 0.003) and executive functioning (median difference = 0.97, ES = 1.24, p = 0.05). Memory recall was not significantly different between the two groups.ConclusionOlder non-demented individuals complaining of memory loss who walked g4000 steps each day had thicker MTL sub-regions and better cognitive functioning than those who walked ≤4000 steps. Future studies should include longitudinal analyses and explore mechanisms mediating hippocampal related atrophy.

Objective Growing evidence supports an association between increased blood pressure and: (a) poor cognitive performance in older adults, and (b) various biomarkers of increased Alzheimer's disease (AD) neuropathology. The objective of this study was to determine whether systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly associated with cognitive functioning in non-demented adults, and to examine in vivo AD pathology as a possible mediator of this association. Methods Positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) provide in vivo measurements of plaque and tangle burden. A total of 101 non-demented older subjects with blood pressure data and FDDNP-PET scans were drawn from a larger study of predictors of cognitive decline. A neuropsychological test battery was used to compute "global cognitive scores" (averaged across five key domains), which served as an index of general cognitive functioning. Results Higher DBP (but not SBP) was significantly associated with lower cognitive scores, controlling for age, sex, antihypertensive medication use, and ApoE genotype (η 2 = 0.06). However, this relationship was no longer significant after introducing FDDNP-PET binding as an additional covariate in the statistical models. In vivo plaque and tangle burden accounted for over 30% of the observed association between higher DBP and poorer cognitive performance. Conclusions By suggesting a mediation of the relationship between DBP and cognitive functioning by FDDNP-PET binding, this study advances our understanding of some potential predictors of cognitive decline in non-demented adults, and underscores the importance of devising early multimodal interventions to more effectively combat degenerative brain disorders.

Introduction The translocase of outer mitochondrial membrane 40 ( TOMM40 ), which lies in linkage disequilibrium with apolipoprotein E ( APOE ), has received attention more recently as a promising gene in Alzheimer's disease (AD) risk. TOMM40 influences AD pathology through mitochondrial neurotoxicity, and the medial temporal lobe (MTL) is the most likely brain region for identifying early manifestations of AD-related morphology changes. Methods In this study, we examined the effects of TOMM40 using high-resolution magnetic resonance imaging in 65 healthy, older subjects with and without the APOE e4 AD-risk variant. Results Examining individual subregions within the MTL, we found a significant relationship between increasing poly-T lengths of the TOMM40 variant and thickness of the entorhinal cortex only in subjects who did not carry the APOE e4 allele. Discussion Our data provide support for TOMM40 variant repeat length as an important contributor to AD-like MTL pathology in the absence of APOE e4.

Overexpression of the amyloid precursor protein (APP)gene on chromosome 21 in Down syndrome (DS) has been linked to increased brain amyloid levels and early-onset Alzheimer’s disease (AD). An elderly man with phenotypic DS and partial trisomy of chromosome 21 (PT21) lacked triplication of APP affording an opportunity to study the role of this gene in the pathogenesis of dementia. Multidisciplinary studies between ages 66–72 years comprised neuropsychological testing, independent neurological exams, amyloid PET imaging with 11C-Pittsburgh compound-B (PiB), plasma Amyloid-β(Aβ)measurements and a brain autopsy examination. The clinical phenotype was typical for DS and his intellectual disability was mild in severity. His serial neuropsychological test scores showed less than a 3% decline as compared to high functioning individuals with DS who developed dementia wherein the scores declined 17–28% per year. No dementia was detected on neurological examinations. On both PiB-PET scans, the patient with PT21 had lower PiB standard uptake values than controls with typical DS or sporadic AD. Plasma Aβ42 was lower than values for demented or non -demented adults with DS. Neuropathological findings showed only a single neuritic plaque and neurofibrillary degeneration consistent with normal aging but not AD. Taken together the findings in this rare patient with PT21 confirm the obligatory role of APPin the clinical, biochemical and neuropathological findings of AD in DS.

Aims This randomized controlled trial sought to determine the financial impact of an initial diagnostic strategy of coronary computed tomography angiography (CCTA) in patients with heart failure (HF) of unknown aetiology. Invasive coronary angiography (ICA) is used to investigate HF patients. CCTA may be a non-invasive cost-effective alternative to ICA. This randomized controlled trial sought to determine the financial impact of an initial diagnostic strategy of coronary computed tomography angiography (CCTA) in patients with heart failure (HF) of unknown aetiology. Methods and results This multicentre, international trial enrolled patients with HF of unknown aetiology. The primary outcome was the cost of CCTA vs. ICA strategies at 12 months. Clinical outcomes were also collected. An ‘intention-to-diagnose’ analysis was performed and a secondary ‘as-tested’ analysis was based on the modality received. Two hundred and forty-six patients were randomized (age = 57.8 ± 11.0 years, ejection fraction = 30.1 ± 10.1%). The severity of coronary artery disease was similar in both groups. In the 121 CCTA patients, 93 avoided ICA. Rates of downstream ischaemia and viability testing were similar for both arms. There were no significant differences in the composite clinical outcomes or quality of life measures. The cost of CCTA trended lower than ICA [CDN −$871 (confidence interval, CI −$4116 to $3028)]. Using an ‘as-tested’ analysis, CCTA was associated with a decrease in healthcare costs (CDN −$2932, 95% CI −$6248 to $746). Conclusion In patients with HF of unknown aetiology, costs were not statistically different between the CCTA and ICA strategies. Clinical Trials.gov NCT01283659

Background Antioxidant nutrients such as the polyphenols in pomegranate juice may prevent neuronal damage from the free radicals produced during normal metabolism. Previous research in animals and a short-term clinical trial in middle-aged and older adults support the potential memory benefits of pomegranate juice; however, the long-term effects of pomegranate juice consumption on cognition have not been studied. Objective In this study, we investigated the long-term effect of pomegranate juice on memory in nondemented middle-aged and older adults. Methods We performed a 12-month, randomized, double-blind, placebo-controlled trial of pomegranate juice in middle-aged and older adults. Two hundred and sixty-one subjects (aged 50-75 y) were randomly assigned to consume pomegranate juice [8 oz (236.5 mL) per day] or a placebo drink (8 oz, matched constituents of pomegranate juice except for pomegranate polyphenols). Memory measures [Brief Visuospatial Memory Test-Revised (BVMT-R) and Buschke Selective Reminding Test (SRT)] were assessed at 6 and 12 mo and analyzed using a mixed-effects general linear model. Results Twenty-eight subjects in the pomegranate juice group and 33 subjects in the placebo group dropped out before completing the study. Baseline variables in the 98 pomegranate juice and 102 placebo group subjects who completed the study did not differ significantly. Group by time interaction was statistically significant for BVMT-R Learning (F[2, 257]= 5.90, P = 0.003; between-group effect size [ES] = 0.45): the change within the pomegranate group was not significant (ES = 0.15), whereas the placebo group showed a significant decline (ES = -0.35). Changes in the other BVMT-R scores as well as the SRT measures were not significantly different between groups. Conclusions Daily consumption of pomegranate juice may stabilize the ability to learn visual information over a 12-mo period. This trial was registered at clinicaltrials.gov as NCT02093130.

Background Several modifiable lifestyle factors have been shown to have potential beneficial effects in slowing cognitive decline. Two such factors that may affect cognitive performance and slow the progression of memory loss into dementia in older adults are cognitive training and physical activity. There are currently no effective treatments for dementia; therefore, preventative strategies to delay or prevent the onset of dementia are of critical importance. Objective The aim of this study was to determine the relative effectiveness of simultaneous performance of memory training and aerobic exercise to a sequential performance intervention on memory functioning in older adults. Methods 55 older adults (aged 60- 75) with subjective memory impairments (non-demented and non-MCI) completed the intervention that consisted of 90-minute small group classes held twice weekly. Participants were randomized to either 4-weeks of supervised strategy-based memory training done simultaneously while stationary cycling (SIM) or sequentially after the stationary cycling (SEQ). Standardized neurocognitive measures of memory, executive functioning, speed of processing, attention, and cognitive flexibility were assessed at baseline and post-intervention. Results The SIM group, but not the SEQ group, had a significant improvement on composite memory following the intervention (t(51) = 2.7, p = 0.01, effect size (ES) = 0.42) and transfer to non-trained reasoning abilities (t(51) = 6.0, ES = 0.49) and complex attention (t(51) = 3.1, p = 0.003, ES = 0.70). Conversely, the SEQ group, but not the SIM, showed significant improvement in executive functioning (t(51) = 5.0, p = 0.0001, ES = 0.96). Conclusion These findings indicate that a 4-week simultaneous memory training and aerobic exercise program is sufficient to improve memory, attention, and reasoning abilities in older adults.

The C677T functional variant in the methylene-tetrahydrofolate reductase (MTHFR) gene results in reduced enzymatic activity and elevated blood levels of homocysteine. Plasma levels of apolipoprotein E (ApoE) are negatively correlated with cerebral amyloid burden, but plasma homocysteine concentrations are associated with increased amyloid-β (Aβ) deposition in the brain. Here, we sought to determine whether associations between low plasma ApoE levels and elevated in-vivo amyloid burden were modulated by carrying the C677T variant. We tested this hypothesis in a large sample of elderly participants from the Alzheimer's Disease Neuroimaging Initiative. We used general linear models to examine associations between plasma homocysteine concentrations, circulating ApoE levels, cerebrospinal fluid concentrations of Aβ, and their modulation by MTHFR and ApoE genotype. Age, sex, and dementia status were included as covariates in all analyses. Higher circulating levels of ApoE predicted increased cerebrospinal fluid concentrations of Aβ, indicating lower in-vivo burden, in C-allele carriers, but not in homozygotes at the C677T variant, who showed significant elevations in plasma homocysteine levels. This modulation by the MTHFR genotype did not remain significant after controlling for ApoE genotype. In T-homozygotes who do not carry the ApoE-e4 allele, the relationship between low plasma ApoE levels and an increased risk of dementia is likely obscured by the presence of elevated plasma homocysteine. This report suggests the value of genotyping patients at the C677T functional variant when using plasma ApoE levels as a preclinical biomarker for Alzheimer's disease.

Author(s): Chen, Stephen T; Siddarth, Prabha; Merrill, David A; Martinez, Jacqueline; Emerson, Natacha D; Liu, Jie; Wong, Koon-Pong; Satyamurthy, Nagichettiar; Giza, Christopher C; Huang, Sung-Cheng; Fitzsimmons, Robert P; Bailes, Julian; Omalu, Bennet; Barrio, Jorge R; Small, Gary W | Abstract: BackgroundOur group has shown that in vivo tau brain binding patterns from FDDNP-PET scans in retired professional football players with suspected chronic traumatic encephalopathy differ from those of tau and amyloid aggregate binding observed in Alzheimer's disease (AD) patients and cognitively-intact controls.ObjectiveTo compare these findings with those from military personnel with histories of mild traumatic brain injury(mTBI).MethodsFDDNP-PET brain scans were compared among 7 military personnel and 15 retired players with mTBI histories and cognitive and/or mood symptoms, 24 AD patients, and 28 cognitively-intact controls. Nonparametric ANCOVAs with Tukey-Kramer adjusted post-hoc comparisons were used to test for significant differences in regional FDDNP binding among subject groups.ResultsFDDNP brain binding was higher in military personnel compared to controls in the amygdala, midbrain, thalamus, pons, frontal and anterior and posterior cingulate regions (p l 0.01-0.0001). Binding patterns in the military personnel were similar to those of the players except for the amygdala and striatum (binding higher in players; p = 0.02-0.003). Compared with the AD group, the military personnel showed higher binding in the midbrain (p = 0.0008) and pons (p = 0.002) and lower binding in the medial temporal, lateral temporal, and parietal regions (all p = 0.02).ConclusionThis first study of in vivo tau and amyloid brain signals in military personnel with histories of mTBI shows binding patterns similar to those of retired football players and distinct from the binding patterns in AD and normal aging, suggesting the potential value of FDDNP-PET for early detection and treatment monitoring in varied at-risk populations.

© 2017 The Authors Objective: Because curcumin's anti-inflammatory properties may protect the brain from neurodegeneration, we studied its effect on memory in non-demented adults and explored its impact on brain amyloid and tau accumulation using 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile positron emission tomography (FDDNP-PET). Methods: Forty subjects (age 51–84 years) were randomized to a bioavailable form of curcumin (Theracurmin® containing 90 mg of curcumin twice daily [N = 21]) or placebo (N = 19) for 18 months. Primary outcomes were verbal (Buschke Selective Reminding Test [SRT]) and visual (Brief Visual Memory Test-Revised [BVMT-R]) memory, and attention (Trail Making A) was a secondary outcome. FDDNP-PET signals (15 curcumin, 15 placebo) were determined in amygdala, hypothalamus, medial and lateral temporal, posterior cingulate, parietal, frontal, and motor (reference) regions. Mixed effects general linear models controlling for age and education, and effect sizes (ES; Cohen's d) were estimated. Results: SRT Consistent Long-Term Retrieval improved with curcumin (ES = 0.63, p = 0.002) but not with placebo (ES = 0.06, p = 0.8; between-group: ES = 0.68, p = 0.05). Curcumin also improved SRT Total (ES = 0.53, p = 0.002), visual memory (BVMT-R Recall: ES = 0.50, p = 0.01; BVMT-R Delay: ES = 0.51, p = 0.006), and attention (ES = 0.96, p < 0.0001) compared with placebo (ES = 0.28, p = 0.1; between-group: ES = 0.67, p = 0.04). FDDNP binding decreased significantly in the amygdala with curcumin (ES = −0.41, p = 0.04) compared with placebo (ES = 0.08, p = 0.6; between-group: ES = 0.48, p = 0.07). In the hypothalamus, FDDNP binding did not change with curcumin (ES = −0.30, p = 0.2), but increased with placebo (ES = 0.26, p = 0.05; between-group: ES = 0.55, p = 0.02). Conclusions: Daily oral Theracurmin may lead to improved memory and attention in non-demented adults. The FDDNP-PET findings suggest that symptom benefits are associated with decreases in amyloid and tau accumulation in brain regions modulating mood and memory.

Near-infrared (near-IR) spectroscopy has been investigated for use in direct measurements of human tissue for the purpose of quantifying clinically relevant analytes such as glucose. Spectra collected by transmitting near-IR light through human tissue reveal the presence of both aqueous components and solid structures within the optical path of the measurement. Developing technology for use in making these measurements requires either the availability of human subjects or an in vitro experimental platform that can effectively simulate the spectroscopic properties of tissue. This paper describes the preparation and testing of films of collagen and keratin, the two proteins that comprise the bulk of the solid material in the human epidermis and dermis. By placing these films in the optical path of a near-IR spectrometer together with an aqueous sample cell, a phantom can be constructed that allows experiments to be performed that simulate noninvasive measurements of tissue. In this work, both constant and variable thickness films are prepared and evaluated by use of a regression fit to spectra of human tissue. The stability and spectral reproducibility of the prepared films are also assessed. The regression fits to the human subject spectra yield values of R(2) ranging from 0.97 to 0.99 and the films are found to yield spectra that vary by less than a 2% relative standard deviation under three different reproducibility tests.

Preventive neuroradiology is a new concept supported by a growing literature. The main rationale of preventive neuroradiology is the application of multi-modal brain imaging towards early and subclinical detection of brain disease and subsequent preventive actions through identification of modifiable risk factors. An insightful example of this is in the area of age-related cognitive decline, mild cognitive impairment and dementia with potentially modifiable risk factors such as obesity, diet, sleep, hypertension, diabetes, depression, supplementation, smoking and physical activity. In studying this link between lifestyle and cognitive decline, brain imaging markers may be instrumental as quantitative measures or even indicators of early disease. The purpose of this article is to provide an overview of the major studies reflecting how lifestyle factors affect the brain and cognition ageing. In this hot topics review we will specifically focus on obesity and physical activity.

Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an N-methyl-D-aspartate receptor (NMDAR) subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition and counteract cognitive deficits at different life stages. © 2014 The Authors.

Objectives: To determine whether psychological well-being in people with mild cognitive impairment (MCI), a risk state for Alzheimer disease (AD), is associated with in vivo measures of brain pathology. Methods: Cross-sectional clinical assessments and positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F18]fluoroethyl)(methyl)amino]-2- naphthyl}ethylidene) malononitrile (FDDNP), a molecule that binds to plaques and tangles, were performed on middle-aged and older adults at a university research institute. Volunteers were aged 40e85 years with MCI (N = 35) or normal cognition (N = 29) without depression or anxiety. Statistical analyses included general linear models, using regional FDDNP-PET binding values as dependent variables and the Vigor-Activity subscale of the Profile of Mood States (POMS) as the independent variable, covarying for age. The POMS is a self-rated inventory of 65 adjectives that describe positive and negative feelings. Results: Scores on the POMS Vigor-Activity subscale were inversely associated with degree of FDDNP binding in the posterior cingulate cortex (r = 0.35, p = 0.04) in the MCI group but not in the control group. Conclusion: Psychological well-being, as indicated by self-reports of greater vigor and activity, is associated with lower FDDNP-PET binding in the posterior cingulate cortex, a region involved in emotional regulation, in individuals with MCI but not in those with normal cognition. These findings are consistent with previous work indicating that deposition of brain amyloid plaques and tau tangles may result in noncognitive and cognitive symptoms in persons at risk for AD. © 2014 American Association for Geriatric Psychiatry.

Current diagnostic and treatment strategies for cognitive decline can help patients maintain cognitive ability and higher levels of function longer. Despite advances in detection and early treatment strategies, many patients do not receive proper assessments and available therapies. A systematic assessment strategy will increase the likelihood of an accurate diagnosis, which can facilitate pharmacologic and non-pharmacologic treatment plans that can have a meaningful impact on prognosis. Available data support the integration of healthy lifestyle strategies in the treatment plan to help to stabilize symptoms and potentially delay future cognitive decline. While investigators continue to pursue more effective detection, treatment, and prevention strategies, the scientific data support the use of symptomatic drug treatments and recommendations for healthy lifestyle behaviors to improve quality of life and potentially stave off future cognitive decline. Success of such healthy lifestyle programs involves educating participants on the connection between lifestyle and disease prevention, offering enjoyable exercises that target the patient's skill level, and providing feedback that motivates participants to continue their healthy behaviors so they become habits.

Across species structural and functional hemispheric asymmetry is a fundamental feature of the brain. Environmental and genetic factors determine this asymmetry during brain development and modulate its interaction with brain disorders. The e4 allele of the apolipoprotein E gene (APOE-4) is a risk factor for Alzheimer's disease, associated with regionally specific effects on brain morphology and function during the life span. Furthermore, entorhinal and hippocampal hemispheric asymmetry could be modified by pathology during Alzheimer's disease development. Using high-resolution magnetic resonance imaging and a cortical unfolding technique we investigated whether carrying the APOE-4 allele influences hemispheric asymmetry in the entorhinal cortex and the hippocampus among patients with Alzheimer's disease as well as in middle-aged and older cognitively healthy individuals. APOE-4 carriers showed a thinner entorhinal cortex in the left hemisphere when compared with the right hemisphere across all participants. Non-carriers of the allele showed this asymmetry only in the patient group. Cortical thickness in the hippocampus did not vary between hemispheres among APOE-4 allele carriers and non-carriers. The APOE-4 allele modulates hemispheric asymmetry in entorhinal cortical thickness. Among Alzheimer's disease patients, this asymmetry might be less dependent on the APOE genotype and a more general marker of incipient disease pathology. © 2013 Elsevier Ireland Ltd.

The relationship of cerebrovascular risk and Alzheimer’s disease (AD) pathology to cognition in pre-dementia has been extensively investigated and is well-established. Cerebrovascular risk can be measured using a Framingham Stroke Risk Profile (FSRP) score, while positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl{ethylidene)malononitrile (FDDNP) measure AD neuropathology (i.e., amyloid-β plaques and tau tangles). Here we report results of 75 healthy non-demented subjects (mean age, 63 years) who underwent neuropsychological testing, physical assessments, and FDDNP-PET scans. Controlling for AD family history, education, and APOE4 status in a general linear model, higher FSRP risk and global FDDNP-PET binding were each associated with poorer cognitive functioning. The interaction of FSRP and global FDDNP-PET binding was not significant in the model, indicating that stroke risk and plaque and tangle burden each contributed to worse cognitive performance. Within our healthy volunteers, age, blood pressure, and antihypertensive medication use were vascular risks that contributed significantly to the above findings. These findings suggest that even mild cerebrovascular risk may influence the extent of cognitive dysfunction in pre-dementia, along with amyloid-β and tau burden.

Objective Exercise and diet impact body composition, but their age-related brain effects are unclear at the molecular imaging level. To address these issues, the authors determined whether body mass index (BMI), physical activity, and diet relate to brain positron emission tomography (PET) of amyloid plaques and tau tangles using 2-(1-(6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile (FDDNP). Methods Volunteers (N = 44; mean age: 62.6 ± 10.7 years) with subjective memory impairment (N = 24) or mild cognitive impairment (MCI; N = 20) were recruited by soliciting for memory complaints. Levels of physical activity and extent of following a Mediterranean-type diet were self-reported. FDDNP-PET scans assessed plaque/tangle binding in Alzheimer disease–associated regions (frontal, parietal, medial and lateral temporal, posterior cingulate). Mixed models controlling for known covariates examined BMI, physical activity, and diet in relation to FDDNP-PET. Results MCI subjects with above normal BMI (>25) had higher FDDNP-PET binding compared with those with normal BMI (1.11(0.03) versus 1.08(0.03), ES = 1.04, t(35) = 3.3, p = 0.002). Greater physical activity was associated with lower FDDNP-PET binding in MCI subjects (1.07(0.03) versus 1.11(0.03), ES = 1.13, t(35) = −3.1, p = 0.004) but not in subjects with subjective memory impairment (1.07(0.03) versus 1.07(0.03), ES = 0.02, t(35) = −0.1, p = 0.9). Healthier diet related to lower FDDNP-PET binding, regardless of cognitive status (1.07(0.03) versus 1.09(0.02), ES = 0.72, t(35) = −2.1, p = 0.04). Conclusion These preliminary findings are consistent with a relationship between risk modifiersand brain plaque/tangle deposition in nondemented individuals and supports maintenance of normal body weight, regular physical activity, and healthy diet to protect the brain during aging. (clinicaltrials.gov; NCT00355498).

Neurotoxicity associated with amyloid and tau protein aggregation could represent a pathophysiological cascade that, along with vascular compromise, may predispose individuals to late-life depression (LLD). In LLD, apathy is common, leads to worsening of functioning, and responds poorly to antidepressant treatment. Better understanding of the pathophysiological mechanisms of apathy in LLD would facilitate development of more effective diagnostic and treatment approaches. In this cross-sectional pilot study, we performed positron emission tomography scans after injection of 2-(1-{6-[(2-[Sixteen depressed elderly volunteers received clinical assessments and [[This pilot study suggests that increased apathy in subjects with LLD may be associated with greater amyloid and/or tau burden in certain brain regions. Future studies in larger samples would elucidate the generalizability of these results, which eventually could lead to improved diagnostic and treatment methods in LLD.

Objectives A cross-sectional study to establish whether a subject's cognitive state can be predicted based on regional values obtained from brain cortical maps of FDDNP Distribution Volume Ratio (DVR), which shows the pattern of beta amyloid and neurofibrillary binding, along with those of early summed FDDNP PET images (reflecting the pattern of perfusion) was performed. Methods Dynamic FDDNP PET studies were performed in a group of 23 subjects (8 control (NL), 8 Mild Cognitive Impairment (MCI) and 7 Alzheimer's Disease (AD) subjects). FDDNP DVR images were mapped to the MR derived hemispheric cortical surface map warped into a common space. A set of Regions of Interest (ROI) values of FDDNP DVR and early summed FDDNP PET (0–6 min post tracer injection), were thus calculated for each subject which along with the MMSE score were used to construct a linear mathematical model relating ROI values to MMSE. After the MMSE prediction models were developed, the models' predictive ability was tested in a non-overlapping set of 8 additional individuals, whose cognitive status was unknown to the investigators who constructed the predictive models. Results Among all possible subsets of ROIs, we found that the standard deviation of the predicted MMSE was 1.8 by using only DVR values from medial and lateral temporal and prefrontal regions plus the early summed FDDNP value in the posterior cingulate gyrus. The root mean square prediction error for the eight new subjects was 1.6. Conclusion FDDNP scans reflect progressive neuropathology accumulation and can potentially be used to predict the cognitive state of an individual.

Logan graphical analysis with cerebellum as reference region has been widely used for the estimation of the distribution volume ratio (DVR) of [18F]FDDNP as a measure of amyloid burden and tau deposition in human brain because of its simplicity and computational ease. However, spurious parametric DVR images may be produced with shorter scanning times and when the noise level is high. In this work, we have characterized a relative-equilibrium-based (RE) graphical method against the Logan analysis for parametric imaging and region-of-interest (ROI) analysis. Methods Dynamic [18F]FDDNP PET scans were performed on 9 control subjects and 12 patients diagnosed with Alzheimer's disease. Using the cerebellum as reference input, regional DVR estimates were derived using both the Logan analysis and the RE plot approach. Effects on DVR estimates obtained at voxel and ROI levels by both graphical approaches using data in different time windows were investigated and compared with the standard values derived using the Logan analysis on a voxel-by-voxel basis for the time window of 35–125 min used in previous studies. Results Larger bias and variability were observed for DVR estimates obtained by the Logan graphical analysis at the voxel level when short time windows (85–125 and 45–65 min) were used, because of high noise levels in voxel-wise parametric imaging. However, when the Logan graphical analysis was applied at the ROI level over those short time windows, the DVR estimates did not differ significantly from the standard values derived using the Logan analysis on the voxel level for the time window of 35–125 min, and their bias and variability were remarkably lower. Conversely, the RE plot approach was more robust in providing DVR estimates with less bias and variability even when short time windows were used. The DVR estimates obtained at voxel and ROI levels were consistent. No significant differences were observed in DVR estimates obtained by the RE plot approach for all paired comparisons with the standard values. Conclusions The RE plot approach provides less noisy parametric images and gives consistent and reliable regional DVR estimates at both voxel and ROI levels, indicating that it is preferred over the Logan graphical analysis for analyzing [18F]FDDNP PET data.

Old age and possession of the APOE -4 allele are the two main risk factors for developing later onset Alzheimer's Disease (AD). Carriers of the APOE -4 allele have known differences in intrinsic functional brain network activity across the life span. These individuals also demonstrate specific regional differences in gray and white matter gross structure. However, the relationship of these variations to whole brain structural network connectivity remains unclear. We performed diffusion tensor imaging (DTI), T1 structural imaging, and cognitive testing on aging APOE -4 noncarriers ( n = 30; mean age = 63.8±8.3) and APOE -4 carriers ( n = 25; mean age = 60.8 ±9.7). Fiber tractography was used to derive whole brain structural graphs, and graph theory was applied to assess structural network properties. Network communication efficiency was determined for each network by quantifying local interconnectivity, global integration, and the balance between these, the small worldness. Relative to noncarriers, APOE -4 carriers demonstrated an accelerated age-related loss of mean local interconnectivity ( r = −0.64, P ≤ 0.01) and regional local interconnectivity decreases in the precuneus ( r = −0.64), medial orbitofrontal cortex ( r = −0.5), and lateral parietal cortex ( r = −0.54). APOE -4 carriers also showed significant age-related loss in mean cortical thickness ( r = −0.52, P < 0.05). Cognitively, APOE -4 carriers had significant negative correlations of age and performance on two episodic memory tasks ( P < 0.05). This genotype-specific pattern of structural connectivity change with age thus appears related to changes in gross cortical structure and cognition, potentially affecting the rate and/or spatial distribution of AD-related pathology.

Amyloid plaques and tau neurofibrillary tangles, the pathological hallmarks of Alzheimer's disease (AD), begin accumulating in the healthy human brain decades before clinical dementia symptoms can be detected. There is great interest in how this pathology spreads in the living brain and its association with cognitive deterioration. Using MRI-derived cortical surface models and four-dimensional animation techniques, we related cognitive ability to positron emission tomography (PET) signal from 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([(18)F]FDDNP), a molecular imaging probe for plaques and tangles. We examined this relationship at each cortical surface point in 23 older adults (10 cognitively intact, 6 with amnestic mild cognitive impairment, 7 with AD). [(18)F]FDDNP-PET signal was highly correlated with cognitive performance, even in cognitively intact subjects. Animations of [(18)F]FDDNP signal growth with decreased cognition across all subjects (http://www.loni.ucla.edu/ approximately thompson/FDDNP/video.html) mirrored the classic Braak and Braak trajectory in lateral temporal, parietal, and frontal cortices. Regions in which cognitive performance was significantly correlated with [(18)F]FDDNP signal include those that deteriorate earliest in AD, suggesting the potential utility of [(18)F]FDDNP for early diagnosis.

Atrophy of the medial temporal lobe (MTL) occurs with aging, resulting in impaired episodic memory. Aerobic fitness is positively correlated with total hippocampal volume, a heavily studied memory-critical region within the MTL. However, research on associations between sedentary behavior and MTL subregion integrity is limited. Here we explore associations between thickness of the MTL and its subregions (namely CA1, CA23DG, fusiform gyrus, subiculum, parahippocampal, perirhinal and entorhinal cortex,), physical activity, and sedentary behavior. We assessed 35 non-demented middle-aged and older adults (25 women, 10 men; 45-75 years) using the International Physical Activity Questionnaire for older adults, which quantifies physical activity levels in MET-equivalent units and asks about the average number of hours spent sitting per day. All participants had high resolution MRI scans performed on a Siemens Allegra 3T MRI scanner, which allows for detailed investigation of the MTL. Controlling for age, total MTL thickness correlated inversely with hours of sitting/day (r = -0.37, p = 0.03). In MTL subregion analysis, parahippocampal (r = -0.45, p = 0.007), entorhinal (r = -0.33, p = 0.05) cortical and subiculum (r = -0.36, p = .04) thicknesses correlated inversely with hours of sitting/day. No significant correlations were observed between physical activity levels and MTL thickness. Though preliminary, our results suggest that more sedentary non-demented individuals have less MTL thickness. Future studies should include longitudinal analyses and explore mechanisms, as well as the efficacy of decreasing sedentary behaviors to reverse this association.

Entorhinal cortex (ERC) volume in adults with mild cognitive impairment has been shown to predict prodromal Alzheimer's disease (AD). Likewise, neuronal loss in ERC has been associated with AD, but not with normal aging. Because ERC is part of a major pathway modulating input to the hippocampus, structural changes there may result in changes to cognitive performance and functional brain activity during memory tasks. In 32 cognitively intact older adults, we examined the relationship between left ERC thickness and functional magnetic resonance imaging (fMRI) activity during an associative verbal memory task. This task has been shown previously to activate regions that are sensitive to aging and AD risk. ERC was manually defined on native space, high resolution, oblique coronal MRI scans. Subjects having thicker left ERC showed greater activation in anterior cingulate and medial frontal regions during memory retrieval, but not encoding. This result was independent of hippocampal volume. Anterior cingulate cortex is directly connected to ERC, and is, along with medial frontal cortex, implicated in error detection, which is impaired in AD. Our results suggest that in healthy older adults, processes that engage frontal regions during memory retrieval are related to ERC structure.

Objectives: Amyloid senile plaques and tau neurofibrillary tangles are neuropathologic hallmarks of Alzheimer disease, which may be associated with mild cognitive impairment (MCI) or mood and anxiety symptoms years before the dementia diagnosis. To address this issue, the authors obtained positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to amyloid plaques and neurofibrillary tangles, to determine whether symptoms of depression and anxiety in nondemented subjects were associated with increased FDDNP-PET binding values. Methods: Forty-three middle-aged and elderly volunteers received clinical and FDDNP-PET assessments. Subjects were nondemented—23 of them were diagnosed with MCI and 20 were cognitively normal. Subjects with a diagnosis of major depression or an anxiety disorder were excluded. Correlations between standardized measures of depressive and anxiety symptoms and regional FDDNP binding values were calculated. Results: The MCI and comparison subjects did not differ by the depression and anxiety scores. In the MCI group, depression scores correlated with lateral temporal and trait anxiety scores correlated with posterior cingulate FDDNP binding. In the comparison group, depression scores correlated with medial temporal, and trait anxiety scores correlated with medial temporal and frontal FDDNP binding. Discussion: This is the first report to demonstrate a relationship between the severity of depression and anxiety symptoms and FDDNP binding values in nondemented middle age and older individuals. The results suggest a relationship between relatively mild mood symptoms and biomarkers of cerebral amyloid and tau deposition and vary according to degree of cognitive impairment. The presence of MCI may signify different pathophysiological mechanisms underlying mood and anxiety symptoms.

Objective: The authors explored whether positron emission tomography (PET) with 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl) amino]-2-naphthyl} ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles in vitro, might identify homogeneous subgroups of persons in middle-aged and older persons with mild cognitive impairment (MCI) or normal cognition. Participants: Fifty-six subjects (MCI, N=29; normal cognition, N=27). Measurements: FDDNP-PET scans were performed. Logan parametric images were produced using cerebellum as a reference region, and relative distribution volumes were obtained for regions of interest (ROIs) known to accumulate plaques and tangles in Alzheimer disease (AD). Cluster analysis was used to identify subgroups of subjects according to FDDNP signal distribution. Once the FDDNP clusters were identified, the authors then characterized the clusters also with respect to diagnosis and cognitive test performances and conducted analyses on cluster differences in these variables. Results: The authors identified three FDDNP clusters: high signal in lateral temporal and posterior cingulate ROIs (high temporal-posterior cingulate HT/PC); low signal in all ROIs (low global [LG] cluster); high frontal and parietal signal with intermediate temporal and posterior cingulate signal (HF/PA). Most MCI subjects belonged to the HT/PC and HF/PA clusters, whereas most cognitively normal subjects were in the LG cluster. On cognitive tests, the HT/PC and the HF/PA clusters performed significantly worse than LG but did not significantly differ from each other. Conclusions: This approach may be useful in identifying potential high-risk imaging cluster patterns. Longitudinal follow-up would be performed to determine the association of these subgroups with diagnostic and functional outcome.

Objective Because anti-inflammatory drugs may delay cognitive decline and influence brain metabolism in normal aging, the authors determined the effects of the cyclooxygenase-2 inhibitor, celecoxib, on cognitive performance and regional cerebral glucose metabolism in nondemented volunteers with mild age-related memory decline. Design Randomized, double-blind, placebo-controlled, parallel group trial with 18-months of exposure to study medication. Setting University research institute. Participants Eighty-eight subjects, aged 40–81 years (mean: 58.7, SD: 8.9 years) with mild self-reported memory complaints but normal memory performance scores were recruited from community physician referrals, media coverage, and advertising. Forty subjects completed the study. Interventions Daily celecoxib dose of 200 or 400 mg, or placebo. Main Outcome Measures Standardized neuropsychological test battery and statistical parametric mapping (SPM) of FDG-PET scans performed during mental rest. Results Measures of cognition showed significant between-group differences in executive functioning (F [1, 30] = 5.06, p=0.03) and language/semantic memory ( F [1, 31] = 6.19, p=0.02), favoring the celecoxib group compared with the placebo group. Concomitantly, FDG-PET scans demonstrated bilateral metabolic increases in prefrontal cortex in the celecoxib group in the vicinity of Brodmann's areas 9 and 10, but not in the placebo group. SPM analyses of the PET data pooled by treatment arm corresponded to a 6% increase in activity over pretreatment levels (p Conclusions These results suggest that daily celecoxib use may improve cognitive performance and increase regional brain metabolism in people with age-associated memory decline.

© 2015, National Academy of Sciences. All rights reserved. Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer' s dementia (AD) ( n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-β] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.

Objective— We sought to examine the risk of mortality associated with nonobstructive coronary artery disease (CAD) and to determine the impact of baseline statin and aspirin use on mortality. Approach and Results— Coronary computed tomographic angiography permits direct visualization of nonobstructive CAD. To date, the prognostic implications of nonobstructive CAD and the potential benefit of directing therapy based on nonobstructive CAD have not been carefully examined. A total of 27 125 consecutive patients who underwent computed tomographic angiography (12 enrolling centers and 6 countries) were prospectively entered into the COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry. Patients, without history of previous CAD or obstructive CAD, for whom baseline statin and aspirin use was available were analyzed. Each coronary segment was classified as normal or nonobstructive CAD (1%–49% stenosis). Patients were followed up for a median of 27.2 months for all-cause mortality. The study comprised 10 418 patients (5712 normal and 4706 with nonobstructive CAD). In multivariable analyses, patients with nonobstructive CAD had a 6% (95% confidence interval, 1%–12%) higher risk of mortality for each additional segment with nonobstructive plaque ( P =0.021). Baseline statin use was associated with a reduced risk of mortality (hazard ratio, 0.44; 95% confidence interval, 0.28–0.68; P =0.0003), a benefit that was present for individuals with nonobstructive CAD (hazard ratio, 0.32; 95% confidence interval, 0.19–0.55; P P =0.287). When stratified by National Cholesterol Education Program/Adult Treatment Program III, no mortality benefit was observed in individuals without plaque. Aspirin use was not associated with mortality benefit, irrespective of the status of plaque. Conclusions— The presence and extent of nonobstructive CAD predicted mortality. Baseline statin therapy was associated with a significant reduction in mortality for individuals with nonobstructive CAD but not for individuals without CAD. Clinical Trial Registration— URL: http://clinicaltrials.gov/ . Unique identifier NCT01443637

Background: Previous linkage studies have shown that chromosome 12 harbors susceptibility genes for late-onset Alzheimer disease (LOAD). However, association studies of several candidate genes on this chromosome region have produced ambiguous results. A recent study reported the association between the glyceraldehyde-3-phosphate dehydrogenase ( GAPD ) gene on chromosome 12p and the risk of LOAD. Methods: The authors conducted family-based and case-control association studies in two independent LOAD data sets on 12 single-nucleotide polymorphisms (SNPs) in the GAPD gene and its paralogs. Results: No association was found of the GAPD gene with LOAD in the family-based data set, but marginal evidence of association was seen in the later-onset subgroup when age at onset was stratified. The SNP rs2029721 in one GAPD pseudogene was also found to be associated with risk for LOAD in the unrelated case-control data set ( p = 0.003). Conclusions: The GAPD gene and its pseudogene may play a role in the development of late-onset Alzheimer disease. However, the effect, if any, is likely to be limited.

We examined the association of mtDNA variation with Alzheimer disease (AD) risk in Caucasians (989 cases and 328 controls) testing the effect of individual haplogroups and single nucleotide polymorphisms (SNPs). Logistic regression analyses were used to assess risk of haplogroups and SNPs with AD in both main effects and interaction models. Males classified as haplogroup U showed an increase in risk (OR = 2.30; 95% CI, 1.03–5.11; P = 0.04) of AD relative to the most common haplogroup H, while females demonstrated a significant decrease in risk with haplogroup U (OR = 0.44; 95% CI, 0.24–0.80; P = 0.007). Our results were independent of APOE genotype, demonstrating that the effect of mt variation is not confounded by APOE4 carrier status. We suggest that variations within haplogroup U may be involved in AD expression in combination with environmental exposures or nuclear proteins other than APOE. © 2004 Published by Elsevier Ireland Ltd.

The prevalence of Alzheimer's disease (AD) and dementia continues to rise. However, a significant number of patients are undiagnosed or untreated. Given the complexities of detecting cognitive impairment and the early signs of AD, this review discusses how advances in brain imaging can help assist in improving overall management. Imaging techniques and surrogate markers may provide unique opportunities to diagnose accurately AD in presymptomatic stages with practical consequences for patients, caregivers, and physicians. The possible outcomes for using imaging and surrogate markers as adjuncts to clinical examination and as screening tools for AD, as well as tangible and intangible advantages to early diagnosis and treatment, will be discussed. The specific value of using advanced serial imaging in patients with a genetic disposition to AD will be evaluated. If neurons can be protected from neurodegenerative damage in early stages, this may preserve patient cognition, function, and quality of life, and may confer considerable societal healthcare benefits.

Background: Similarities between Alzheimer disease (AD) and Parkinson disease (PD) suggest a possible role for apolipoprotein E (APOE) in PD. Most previous studies seeking to establish such a link used case-control datasets and results have been inconsistent. Objective: To investigate APOE’s role in PD using family-based association analyses. Methods: APOE functional polymorphisms were genotyped for 658 PD affected families, including 282 multiplex and 376 singleton families. The pedigree disequilibrium test (PDT) and the genotype-PDT were used to test the risk effect of APOE. The Monks-Kaplan test was used to evaluate the effect of APOE on age at onset of PD. Results: APOE was significantly associated with risk of developing PD. Stratified analysis revealed that APOE was most strongly associated with families with a positive PD family history (global p = 0.003). Like AD, the APOE-4 allele increases disease risk while the APOE-3 allele decreases risk. We detected a positive association of APOE-3 ( p = 0.019) and a negative association of APOE-4 ( p = 0.015) with age at onset in PD. Conclusions: The APOE-4 allele increases risk and decreases age at onset of PD, an association that may not be dependent upon cognitive impairment.

OBJECTIVE Because the apolipoprotein epsilon4 (APOE-epsilon4) allele or depressive symptoms may increase the risk for development of Alzheimer disease (AD), the authors assessed APOE-epsilon4 status, baseline level of depressive symptoms, and subsequent cognitive decline in middle-aged and older persons without dementia. METHODS The 49 subjects (age range: 51-85 years) included 20 with and 29 without APOE-epsilon4. Baseline and follow-up neuropsychological assessments determined the degree of cognitive decline. RESULTS Baseline mild depressive symptoms were greater in APOE-epsilon4 carriers than in non-carriers. The subject groups demonstrated significant cognitive decline at follow-up. APOE-epsilon4 carriers showed a significantly greater rate of verbal memory decline than non-carriers. Baseline depressive symptoms, however, did not predict future cognitive decline. CONCLUSIONS These results suggest that APOE-epsilon4 carriers may have a greater severity of depressive symptoms than non-carriers. The APOE-epsilon4 allele (but not baseline mild depressive symptoms) is associated with verbal memory decline in middle-aged and older persons. Because of the limited range of depression scores in our sample, these findings should be interpreted with caution and not be generalized to patients with syndromal depression.

It is difficult to accurately forecast the clinical course of many patients presenting with mild cognitive problems. The utility in prognostic evaluation of various parameters of brain structure and function that can now be noninvasively measured remains to be clearly defined. The present work examined the value of regional cerebral metabolism, assessed with positron emission tomography (PET) and [ 18 F]fluoro-2-deoxyglucose, in this context. PET scans of 167 patients (mean Mini-Mental State Examination (MMSE)=24 of 30 possible points) were classified as being positive or negative for evidence of progressive dementia. Results of scans were compared to patients' subsequent clinical course in general and in particular, to their changes in MMSE scores, for up to 10 years following PET. Data were further stratified according to the predictions of referring physicians based upon clinical assessments that had been performed up until the time of PET. Among those patients for whom a progressive dementing course had been predicted by PET criteria (but not those who were predicted by PET criteria to remain stable) a significant decline in general cognitive performance and MMSE scores occurred in the period following PET. Among those patients predicted by clinical criteria to have a progressive dementing illness, 94% of those with positive PET scans did suffer a progressive decline, while only 25% of those with negative scans progressed (relative risk 3.8). Similarly, among those patients who had been predicted by clinical criteria to remain cognitively stable, 74% of those with positive PET scans nevertheless suffered progressive decline, compared with 4% of those with negative PET scans (relative risk 18.4). These data indicate that evaluation of brain metabolism by PET in appropriately selected patients may improve the accuracy of clinical prognostic assessment.

Alzheimer disease (AD) is a complex disorder characterized by a wide range, within and between families, of ages at onset of symptoms. Consideration of age at onset as a covariate in genetic-linkage studies may reduce genetic heterogeneity and increase statistical power. Ordered-subsets analysis includes continuous covariates in linkage analysis by rank ordering families by a covariate and summing LOD scores to find a subset giving a significantly increased LOD score relative to the overall sample. We have analyzed data from 336 markers in 437 multiplex (⩾2 sampled individuals with AD) families included in a recent genomic screen for AD loci. To identify genetic heterogeneity by age at onset, families were ordered by increasing and decreasing mean and minimum ages at onset. Chromosomewide significance of increases in the LOD score in subsets relative to the overall sample was assessed by permutation. A statistically significant increase in the nonparametric multipoint LOD score was observed on chromosome 2q34, with a peak LOD score of 3.2 at D2S2944 (P=.008) in 31 families with a minimum age at onset between 50 and 60 years. The LOD score in the chromosome 9p region previously linked to AD increased to 4.6 at D9S741 (P=.01) in 334 families with minimum age at onset between 60 and 75 years. LOD scores were also significantly increased on chromosome 15q22: a peak LOD score of 2.8 (P=.0004) was detected at D15S1507 (60 cM) in 38 families with minimum age at onset ⩾79 years, and a peak LOD score of 3.1 (P=.0006) was obtained at D15S153 (62 cM) in 43 families with mean age at onset >80 years. Thirty-one families were contained in both 15q22 subsets, indicating that these results are likely detecting the same locus. There is little overlap in these subsets, underscoring the utility of age at onset as a marker of genetic heterogeneity. These results indicate that linkage to chromosome 9p is strongest in late-onset AD and that regions on chromosome 2q34 and 15q22 are linked to early-onset AD and very-late-onset AD, respectively.

Performance on individual Mini-Mental State Examination (MMSE) items can predict incident Alzheimer's disease (AD). The purpose of the current study is to determine whether, in nondemented persons with and without the apolipoprotein E-4 (APOE-4) genetic risk for AD, a subset of MMSE items predict cognitive decline. Fifty-four nondemented subjects, 23 with at least one copy of the APOE-4 allele and 31 without APOE-4, were given the MMSE and cognitive tests at baseline and 2-year follow-up. MMSE total score and a subset of MMSE items including delayed recall, serial 7s, pentagon, and orientation to time and place were used to predict change on cognitive tests. The subset of MMSE items significantly predicted decline in visuo-spatial construction and naming in APOE-4 carriers but not in noncarriers. Performance on a subset of MMSE items, combined with APOE-4 genotype, may aid in identifying high-risk persons for research or follow-up. ( J Geriatr Psychiatry Neurol 2003; 16:67-73)

OBJECTIVES: Previous studies have suggested sex differences in mood and cognition and that estrogen effects may partially explain such differences. In this study, we explore sex differences for a range of mood symptoms and for neuropsychological performance in men and postmenopausal women and assess the potential influence of estrogen on these measures. DESIGN: Cross-sectional study of men and women examining mood, neuropsychological test data, and estrogen replacement therapy (ERT) use. SETTING: Outpatient study at an urban teaching hospital with subjects recruited from the community. PARTICIPANTS: All subjects (N = 96) were between the ages of 57 and 75 and included 31 women using ERT, 16 non-ERT users, and 49 men. Subjects did not have major depression and were nondemented. MEASUREMENT: The three groups were compared according to profile of mood states and neuropsychological performance, and statistical analyses were controlled for socioeconomic status, age, and education level. RESULTS: Female ERT users were less depressed and less angry and performed better on measures of verbal fluency and working memory than the other subject groups. CONCLUSION: Postmenopausal estrogen use is associated with better mood and cognitive performance on tasks of fluency and working memory. These results suggest that estrogen should be examined as a potentially critical variable influencing late-life sex differences in mood and cognition.

Memory changes cause concern to many patients as they grow older. Gary Small provides reassurance and gives a strategy for assessing age related memory loss and protecting brain health As doctors and scientists have focused more attention on Alzheimer's disease and related dementias, patients are expressing greater concern about their common, age related memory changes. When results of new research on early detection and prevention reach a wider audience, our patients often come to the office with questions about what they can do to preserve their memory abilities as they age. Many of today's doctors trained during a time when minimal information was provided on these topics during their medical training. This paper will provide a practical strategy for assessing age related memory loss and will discuss interventions that may or may not protect brain health. #### Summary points Patients with mild memory loss are common in clinical practice; if their symptoms warrant a diagnosis of dementia, treatment with cholinesterase inhibitor drugs is needed Doctors need to be cautious about unproved treatments for slowing brain ageing because of potential side effects Lifestyle choices may protect people with mild forms of age related memory loss from future decline: essentially, what is healthy for the body is healthy for the brain The risks of these interventions are minimal and are not likely to outweigh the many benefits The viewpoints presented were based on my clinical experience and a databased literature review. I selected articles with Medline searches using key words relevant to the theme of this review, emphasising peer reviewed journals and data from controlled clinical trials or methodologically sound epidemiological studies when available. With age comes the increasing likelihood of developing memory loss. The mildest form, age associated memory impairment, is characterised by self perception of memory loss and a standardised memory test score …