Hanna Blazel

Effects of Simvastatin on Cerebrospinal Fluid Biomarkers and Cognition in Middle-Aged Adults at Risk for Alzheimer's Disease

BACKGROUND Statins reduce amyloid-beta (Abeta) levels in the brain and cerebrospinal fluid (CSF) in animals and may thereby favorably alter the pathobiology of AD. It is unclear if statins modify Abeta metabolism or improve cognition in asymptomatic middle-aged adults at increased risk for AD. METHODS In a 4-month randomized, double-blind, controlled study, we evaluated the effects of simvastatin 40 mg daily vs. placebo on CSF Abeta42 levels and cognition in 57 asymptomatic middle-aged adult children of persons with AD. RESULTS Compared to placebo, individuals randomized to simvastatin for 4 months had similar changes in CSF Abeta42 (p=0.344) and total tau levels (p=0.226), yet greater improvements in some measures of verbal fluency (p=0.024) and working memory (p=0.015). APOE4 genotype, gender, and vascular risk factors were associated with CSF biomarker levels, but did not modify treatment effects. CONCLUSION In asymptomatic middle-aged adults at increased risk for AD, simvastatin use improved selected measures of cognitive function without significantly changing CSF Abeta42 or total tau levels. Further studies are needed to clarify the impact of higher dose and/or longer duration statin therapy on not only Abeta metabolism, but also other preclinical processes related to the development of AD.

Cerebrospinal fluid sphingolipids, β-amyloid, and tau in adults at risk for Alzheimer's disease

Cellular studies suggest sphingolipids may cause or accelerate amyloid-beta (Aβ) and tau pathology but in vivo human studies are lacking. We determined cerebrospinal fluid levels of sphingolipids (ceramides and sphingomyelins), amyloid-beta (Aβ1-42, AβX-38, AβX-40, and AβX-42) and tau (T-tau and p-tau181) in 91 cognitively normal individuals, aged 36-69 years, with a parental history of Alzheimers disease. The 18-carbon acyl chain length ceramide species was associated with AβX-38 (r = 0.312, p = 0.003), AβX-40 (r = 0.327, p = 0.002), and T-tau (r = 0.313, p = 0.003) but not with AβX-42 (r = 0.171, p = 0.106) or p-tau (r = 0.086, p = 0.418). All sphingomyelin species correlated (most p < 0.001) with all Aβ species and T-tau; many also correlated with p-tau. Results remained in regression models after controlling for age and APOE genotype. These results suggest in vivo relationships between cerebrospinal fluid ceramides and sphingomyelins and Aβ and tau levels in cognitively normal individuals at increased risk for Alzheimers disease, indicating these sphingolipids may be associated with early pathogenesis.

Effects of atorvastatin on cerebral blood flow in middle-aged adults at risk for Alzheimer's disease: a pilot study.

BACKGROUND/AIMS Hypercholesterolemia in midlife increases risk for Alzheimers disease (AD) and contributes to cerebrovascular dysregulation - an early finding in preclinical AD pathology. Statins improve vascular reactivity, but it is unknown if they increase regional cerebral blood flow (CBF) in individuals at risk for AD. METHODS In a randomized, controlled, double-blind pilot study, 16 asymptomatic middle-aged adults with parental history of AD were randomized to atorvastatin or placebo daily for 4 months. At baseline and month 4, regional CBF was measured using arterial spin-labeling magnetic resonance imaging and endothelial function was measured using brachial artery ultrasound. RESULTS At baseline, participants with low HDL-cholesterol, higher global vascular risk, and greater endothelial dysfunction had reduced regional CBF in areas of the brain related to memory and learning (all p < 0.03). Using voxel-based analysis, 4 months of atorvastatin increased CBF in bilateral hippocampi, fusiform gyrus, putamen and insular cortices compared to placebo. CONCLUSION In this pilot study, atorvastatin increased regional CBF in persons at risk for AD. Further research is warranted to confirm whether statins increase CBF in areas of the brain related to memory and learning and whether such perfusion changes are associated with a delay in the onset of AD. CLINICAL TRIAL REGISTRATION http://clinicaltrials.gov Identifier: NCT00751907.

COHORT AND RACE DIFFERENCES IN FACTORS ASSOCIATED WITH ATTRITION IN LONGITUDINAL STUDIES OF ALZHEIMER’S DISEASE

Radio advertising 69.01% 50.98% Registries 61.97% 57.45% Television advertising 50.70% 73.68% Dorothy Farrar Edwards, Carey E. Gleason, Hanna Blazel, Cynthia M. Carlsson, Alice Spalitta, Susan Stark, Sanjay Asthana, Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; William S. Middleton Memorial Veterans’ Hospital, Madison, WI, USA; University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Wisconsin Alzheimer’s Disease Research Center, Madison, WI, USA; Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Washington University Alzheimer’s Disease Research Center, St. Louis, MO, USA; Geriatric Research Education and Clinical Center, W.S. Middleton Memorial Veterans Hospital, Madison, WI, USA. Contact e-mail: dfedwards@wisc.edu

KEY ELEMENTS SUPPORTING RECRUITMENT AND RETENTION OF UNDERREPRESENTED GROUPS INTO RESEARCH: OUR EXPERIENCE IN THE AFRICAN AMERICAN COMMUNITY

care partner of a person with Alzheimer’s/another dementia); 2) multisensory enrichment group for person with dementia held in parallel with care partner support group; 3) early journey support group for persons with recently diagnosed mild cognitive impairment or early stage Alzheimer’s who attend with their primary family care partner (spouse and/or adult child); and 4) fronto-temporal dementia support group for care partners only. Groups lasts 90 minutes, are held weekly for 8-10 consecutive weeks, have 8-16 participants, and are led by licensed clinical social workers/counselors. Weekly sessions are guided by a unique handout that facilitates decompression (talking about experience of being a person with dementia or care partner), education (various topics addressing common cognitive, physical, and emotional challenges), problem solving (skills for addressing behavioral and psychological symptoms of dementia), and relationship building (strengthening relationships between person with dementia, care partner, and family members). After completing an 8-10-week support group, the person with dementia and their care partner have the opportunity for individual, couple, or family counseling. Care partners can also participate in a 90 minute monthly maintenance support group that focuses on decompression. The 8-10 week groups are offered three times a year and feed into the monthly group, resulting in a comprehensive and sustainable support group program for person with dementia and their care partners. Results: Over last 6 years, the usual attrition rate per group is 15-20%. Participants evaluate their support group experience when group ends. Over 90% rate the following as “5” on a Likert scale of 1 (not at all) to 5 (very much) for these measures: group met expectations, I felt safe and accepted, knowledge of dementia was increased, coping skills enhanced, and facilitators were knowledgeable/compassionate. Conclusions: A comprehensive, sustainable support group program for person with dementia and family care partners is feasible and beneficial. Challenges and future plans will be discussed.

IMPACT OF SIMVASTATIN ON CEREBRAL BLOOD FLOW, PULSATILITY INDEX, AND ALZHEIMER’S DISEASE BIOMARKERS: A CLINICAL TRIAL

allele status, treatment group, and baseline LDL cholesterol and systolic BP, change in AIx was not associated with changes in PI (p values >0.74). Conclusions:AIx measured using radial arterial tonometry and cerebral PI measured by 4D Flow MRI were not significantly correlated at baseline, nor were changes in these measures after 18 months of simvastatin or placebo. These findings suggest that, in this population at risk for AD, radial artery tonometry and central measures of arterial stiffness may not be linked linearly. Further research is needed to elucidate how cerebral autoregulation and systemic vascular disease may contribute to central arterial dysregulation in the context of AD.

DEMOGRAPHIC FACTORS INFLUENCE PARTICIPATION IN LUMBAR PUNCTURES

Calgary (Canada); or Charit e Hospital and University Hospital Magdeburg (Germany). Biomarkers of neuronal injury (total tau, VILIP-1), inflammation (YKL-40), and neurotransmission (neurogranin, SNAP-25) were compared between patients and controls (univariate ANCOVA), controlling for age. Results: Median ageat-symptomatic onset of AME was 30.5 years (range, 11-85); 34/ 46 (74%) patients were female. Patients with NMDAR encephalitis were younger (27 years, 4.0-41.8) than patients with LGI1/ CASPR2 AME (70.4 years, 60.6-83.2; p<0.001). Markers of neuronal injury were similar (mean total tau [95%CI]: 22.6 pg/ml [16.8-28.5]; vs. 18.2 pg/ml [12.9-23.4]; p1⁄40.27) or decreased (VILIP-1: 47.2 pg/ml [34.5-59.8]; vs. 124.3 pg/ml [113.0-135.6]; p<0.001) in the CSF of AME patients versus controls. The neuroinflammatory biomarker YKL-40 was elevated in AME patient CSF (YKL-40: 315.0 pg/ml [272.0-358.1] vs. 177.7 pg/ml [139.6-215.9]; p<0.001), while markers of neurotransmission were decreased (SNAP-25: 1.63 pg/ml [1.29-1.97] vs. 3.22 pg/ml [2.92-3.53], p<0.001; neurogranin: 615.3 pg/ml [375-854.7] vs. pg/ml 1504.8 [1290.2-1719.3], p<0.001). VILIP-1 levels differentiated patients with AME associated with NMDAR (27.0 pg/ml [12.9-41.1]) from LGI1/CASPR2 autoantibodies (84.5 pg/ml [47.1-121.8]; p1⁄40.02). No other biomarker differences were observed between AME patients. Conclusions:Biofluid biomarkers validated in patients with neurodegenerative dementing illnesses may be applied to improve diagnosis and predict outcomes in patients with other causes of cognitive impairment. Specifically, these biomarkers suggest that neuronal integrity is acutely maintained in AME patients. Low-levels of biomarkers of neurotransmission may reflect antibody-mediated internalization of cell-surface receptors, and may represent an acute correlate of autoimmune-mediated synaptic dysfunction underlying cognitive sequelae in recovering patients.

RELATIONSHIP BETWEEN AORTIC AUGMENTATION INDEX BY RADIAL ARTERY TONOMETRY AND CEREBRAL PULSATILITY INDEX IN INDIVIDUALS AT RISK FOR ALZHEIMER’S DISEASE

Background:Autopsy studies have consistently reported that neurofibrillary tau tangles, rather than the amyloid-b neuritic plaques, are associated AD neurodegeneration pattern. Furthermore, higher rates of neurodegeneration have prognostic value in predicting conversion frommild cognitive impairment to AD and increased risk of developing AD dementia in cognitively normal individuals. Methods:We obtained longitudinal-sectional multimodality neuroimaging data(structural-MRI for cortical thickness and flortaucipirPET for tau pathology) at two time-points (1.2960.33 years apart) from 25 cognitively healthy elderly individuals(9 Ab+) and 20 older individuals withMCI(8 Ab+) from the ADNI study. Time difference between MRI and PET imaging sessions was 1.2161.37 months at baseline and 0.35 6 0.53 months at the follow-up visit. Within each group, separate sparse whole brain multimodality canonical correlation analyses were performed to assess 1) the covarying brain patterns of current levels of tau pathology and rates of cortical thinning from a prognostic perspective, and 2) the covarying brain patterns of rates of tau pathology accumulation and rates of cortical thinning from a pathophysiological progression perspective. Results: Higher levels of current tau pathology in medial temporal and inferior temporal regions were associated with greater rates of cortical thinning in prefrontal cortex (predominantly regions highly associated with attention) with relatively lower cortical thinning rates in medial temporal regions in cognitively normals, and 2) higher rates of temporo-occipital and medial orbitofrontal cortical thinning in MCI(Figure 1).In contrast, greater rates of cortical thinning in prefrontal cortex as well as central insula were associated with a pattern of higher levels of rates of tau accumulation in superior frontal regions in cognitively normals (Figure 2). In MCIs, increased focal rates of cortical thinning in dorsolateral frontal, inferior parietal lobule, and inferior temporal cortex were associated with higher levels of rates of tau accumulation in inferior parietal lobule(Figure 2). Conclusions: Our work found that rates of neurodegeneration were associated with both concurrent and longitudinal tau accumulation in distant brain regions. These results are consistent with previously proposed model of pathophysiological spread of AD in brain networks. Validation of our findings in larger sample size cohorts might elucidate the temporal ordering of tau-PET relative to structural-MRI as imaging markers of disease progression and prognosis.

THE WRAP-AROUND APPROACH: A NOVEL RENTENTION STRATEGY IN THE AA-FAIM STUDY

patients (13.3%) were diagnosed with malignancy (bronchogenic carcinoma, non-Hodgkin’s lymphoma and metastatic carcinoma with unknown primary). On six month follow up, mortality was 10% and all the patients who died were diagnosed with malignancy. One patient required readmission following discharge in the follow up period. Conclusions:Care planning of AD patients require management of chronic and acute medical comorbidities and AD patients who require hospital admission have high short-term mortality rate.

COMPARING COGNITIVE BATTERIES: UNIFORM DATA SET 2 (UDS-2) AND UNIFORM DATA SET 3 (UDS-3) IN NON-HISPANIC WHITE PARTICIPANTS AND THOSE FROM UNDERREPRESENTED GROUPS ENROLLED IN THE WISCONSIN ALZHEIMER'S DISEASE RESEARCH CENTER'S CLINICAL CORE

Boston.Namin Total.Score Category.Fluen Raw.Score WAIS.R...Digi WMS.R...Log A.Raw.Scor WMS.R...Log A.Raw.Scor MMSE... Tota Trail.Making.T Trail.Making.T WAIS.R...Digi Score WAIS.R...Digi Longest.Spa WAIS. R...Dig Raw.Score WAIS.R...Digi Longest.Spa Category.Fluen Raw.Score Boston.Namin Score Standard devia Proportion of Cumulative Pr UNIFORM DATA SET 2 (UDS-2) AND UNIFORM DATA SET 3 (UDS-3) IN NONHISPANIC WHITE PARTICIPANTS AND THOSE FROM UNDERREPRESENTED GROUPS ENROLLED IN THE WISCONSIN ALZHEIMER’S DISEASE RESEARCH CENTER’S CLINICAL CORE