Nare Torosyan

Neuronuclear Imaging in the Evaluation of Dementia and Mild Decline in Cognition

Recently, the National Institute on Aging and the Alzheimers Association identified specific structural and functional neuroimaging findings as valuable markers of biological processes occurring in the human brain, especially processes that herald impending dementia caused by Alzheimers disease (AD) in its prodromal form. In particular, the imaging modalities of magnetic resonance imaging and positron emission tomography (PET) were singled out, along with certain biomarkers in cerebrospinal fluid, to serve this purpose. We review the clinical tests available for neuropsychologic evaluation and in cases when the differential diagnosis for the causes of cognitive impairment is difficult to make, we consider biomarkers, beginning with cerebrospinal fluid, for assessment of cognitive decline. For more direct information on dementia-related pathologic changes in brain tissue, structural features observed in magnetic resonance imaging scans are regarded. We next discuss the use of single-photon emission computed tomography for evaluating functional changes. Then, pertinent to the recent National Institute on Aging and the Alzheimers Associations consensus statement on the diagnosis of prodromal AD, we focus on assessing the cerebral metabolic changes associated with neurodegenerative diseases that are identified with fluorodeoxyglucose PET, as well as consider the most appropriate roles for amyloid imaging based on recent studies examining the use of PET with tracers having higher retention in brain tissue-harboring plaques composed of insoluble beta-amyloid. We also consider the leading causes for the current underuse of neuronuclear imaging in evaluating patients with cognitive problems, along with strategies for combating them. Finally, we suggest an overall diagnostic algorithm to guide optimal use of all the neuroimaging tools in assessing patients with cognitive decline.

Longitudinal Relationships between Caloric Expenditure and Gray Matter in the Cardiovascular Health Study

Background: Physical activity (PA) can be neuroprotective and reduce the risk for Alzheimer’s disease (AD). In assessing physical activity, caloric expenditure is a proxy marker reflecting the sum total of multiple physical activity types conducted by an individual. Objective:To assess caloric expenditure, as a proxy marker of PA, as a predictive measure of gray matter (GM) volumes in the normal and cognitively impaired elderly persons. Methods: All subjects in this study were recruited from the Institutional Review Board approved Cardiovascular Health Study (CHS), a multisite population-based longitudinal study in persons aged 65 and older. We analyzed a sub-sample of CHS participants 876 subjects (mean age 78.3, 57.5% F, 42.5% M) who had i) energy output assessed as kilocalories (kcal) per week using the standardized Minnesota Leisure-Time Activities questionnaire, ii) cognitive assessments for clinical classification of normal cognition, mild cognitive impairment (MCI), and AD, and iii) volumetric MR imaging of the brain. Voxel-based morphometry modeled the relationship between kcal/week and GM volumes while accounting for standard covariates including head size, age, sex, white matter hyperintensity lesions, MCI or AD status, and site. Multiple comparisons were controlled using a False Discovery Rate of 5 percent. Results: Higher energy output, from a variety of physical activity types, was associated with larger GM volumes in frontal, temporal, and parietal lobes, as well as hippocampus, thalamus, and basal ganglia. High levels of caloric expenditure moderated neurodegeneration-associated volume loss in the precuneus, posterior cingulate, and cerebellar vermis. Conclusion:Increasing energy output from a variety of physical activities is related to larger gray matter volumes in the elderly, regardless of cognitive status.

Examining the impact of grape consumption on brain metabolism and cognitive function in patients with mild decline in cognition: A double-blinded placebo controlled pilot study

Background Natural compounds in grapes such as resveratrol are known for their antioxidant and anti‐inflammatory properties. Some studies have shown a potential role for grapes or wine in slowing cognitive decline and other effects of aging. However, well‐controlled experimental data obtained in human subjects are still in need of further development. Here we aimed to systematically assess effects of grapes on regional cerebral metabolism. Methods Ten subjects with mild decline in cognition (mean, 72.2 ± 4.7 years; 50% female) were included in this analysis. Participants were randomized into an active grape formulation arm or a placebo arm which consumed a formulation free of polyphenols for six months. Cognitive performance was measured through neuropsychological assessments performed at baseline and 6 months after initiation of therapy. Changes in brain metabolism occurring with each therapy regimen were assessed by brain PET scans with the radiotracer [F‐18] fluorodeoxyglucose (FDG), obtained during initial evaluation and 6 months later. Standardized volumes of interest (sVOI) and statistical parametric mapping (SPM) methods were applied to FDG‐PET scans to identify significant regional cerebral metabolic changes. Results In contrast to participants taking the active grape formulation, who displayed no significant decline in metabolism, the placebo arm underwent significant metabolic decline in sVOIs of the right posterior cingulate cortex (p = 0.01), and left superior posterolateral temporal cortex (p = 0.04). SPM analyses also found significant declines in the placebo group, particularly in left prefrontal, cingulate, and left superior posterolateral temporal cortex (p < 0.01) with stable brain metabolism in the active formulation arm. No significant differences were seen in scores on the neuropsychological battery of tests between the two groups. However, metabolism in right superior parietal cortex and left inferior anterior temporal cortex was correlated with improvements in attention/working memory, as measured with WAIS‐III Digital Span within the active formulation group (r = − 0.69, p = 0.04). Conclusions The placebo arm had declines in regions of the brain known to be significantly affected in the early stages of Alzheimers disease, while the active formulation group was spared such decline. This suggests a protective effect of grapes against early pathologic metabolic decline. Highlights72 g of daily grape intake for 6 months have a protective effect on brain metabolism.Supplementation with grapes did not change neuropsychological battery measures.Polyphenol studies with more mildly impaired adults for longer periods are needed.

Changes in regional cerebral blood flow associated with a 45 day course of the ketogenic agent, caprylidene, in patients with mild to moderate Alzheimer's disease: Results of a randomized, double-blinded, pilot study

Background Caprylidene is a ketogen that, when metabolized, produces the ketones beta‐hydroxybutyrate and acetoacetate, which can cross the blood brain barrier. It has been hypothesized that ketone bodies can be used as an alternate energy source by neurons with impaired glucose utilization. Caprylidene has been shown to improve cognition in patients with mild‐to‐moderate Alzheimers disease (AD) who lacked an AD‐predisposing allele (&egr;4) of the gene for apolipoprotein E. In this pilot study, we examined the effects of caprylidene on regional cerebral blood flow (rCBF) in patients with mild to moderate AD. Methods Sixteen subjects with mild‐to‐moderate AD, based on NINCDS‐ADRDA criteria, were enrolled in a double‐blinded, placebo‐controlled, randomized clinical trial. Fourteen subjects received treatment with caprylidene, and 2 subjects were given placebo. Subjects received 4 15O‐water PET scans over the course of the study to assess rCBF: once before receiving a standard caprylidene or placebo dose and 90 min after the dose, on the first day and after 45 days of daily caprylidene or placebo consumption. The scans were examined by standardized volumes of interest (sVOI) and voxel‐based statistical parametric mapping (spm) methods of analysis. Results Subjects lacking an &egr;4 allele had significantly elevated rCBF in the left superior lateral temporal cortex by sVOI analysis after adopting a caprylidene diet for 45 days (p = 0.04), which was further corroborated by spm. The anterior cerebellum, left inferior temporal cortex, and hypothalamus were also found by spm to be regions of long‐term increase in rCBF in these subjects. In contrast, patients who possessed the &egr;4 allele did not display these changes in rCBF. Conclusion Daily ingestion of caprylidene over 45 days was associated with increased blood flow in specific brain regions in patients lacking an apolipoprotein &egr;4 allele. HighlightsA ketogen‐based approach to improve cognitive function in dementia patients is proposed.The strategy relies on daily caprylidene supplementation for 45 days.Effect on regional cerebral blood flow differs by apolipoprotein E4 status.

ASSESSING IMPACT OF DIABETIC PROPENSITY AND SEX IN SUBJECTS WITH NORMAL OR IMPAIRED COGNITION ON TRAJECTORIES OF METABOLIC DECLINE IN BROCA’S AREA AND TEMPORAL CORTEX

APOE4 7.5 (6.3, 8.6) 2.9 (1.2,4.6) Female sex 1.7 (0.7, 2.8) 0.6 (-1.0, 2.2) Terry M. Therneau, Stephen D. Weigand, Heather J. Wiste, Val J. Lowe, Prashanthi Vemuri, Michelle M. Mielke, Rosebud O. Roberts, David S. Knopman, Ronald C. Petersen, Clifford R. Jack, Jr,, Mayo Clinic, Rochester, MN, USA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Department of Neurology, Mayo Clinic, Rochester, MN, USA. Contact e-mail: therneau@mayo.edu

BIN1 AND CR1 VARIANTS AFFECT COGNITIVE PERFORMANCE, NEURODEGENERATION, AND BRAIN AMYLOIDOSIS IN ADNI SUBJECTS

Anna Blanken, Daniel H. Silverman, Nare Torosyan, Manogna Manne, Beata Durcanova, Andrew J. Saykin, Clifford R. Jack, Liana G. Apostolova, UCLA, Los Angeles, California, United States; University of California, Los Angeles, Los Angeles, California, United States; Indiana University School of Medicine, Indianapolis, Indiana, United States; Mayo Clinic, Rochester, Minnesota, United States. Contact e-mail: ablanken@mednet.ucla.edu

Prognostic value of FDG-PET scans for predicting cognitive decline in MCI subjects, combining visual analysis with a quantitative index generated with clinically routine software

P4-353 PROGNOSTIC VALUE OF FDG-PET SCANS FOR PREDICTING COGNITIVE DECLINE IN MCI SUBJECTS, COMBININGVISUALANALYSISWITH A QUANTITATIVE INDEX GENERATEDWITH CLINICALLY ROUTINE SOFTWARE Daniel Silverman, Nare Torosyan, Eve Ystang, Sravya Mallam, Regina Ahn, Magnus Dahlbom, Kelsey Mason, UCLA, Los Angeles, California, United States; University of California, Los Angeles, Los Angeles, California, United States; David Geffen School of Medicine, UCLA, Los Angeles, California, United States; David Geffen School of Medicine, UCLA, Los Angeles, California, United States.