Catherine E. Munro

Biomarker validation of a decline in semantic processing in preclinical Alzheimer's disease.

OBJECTIVE Differentially worse performance on category versus letter fluency suggests greater semantic versus retrieval difficulties. This discrepancy, combined with reduced episodic memory, has widespread clinical utility in diagnosing Alzheimers disease (AD). Our objective was to investigate whether changes in semantic processing, as measured by the discrepancy between category and letter fluency, was detectable in preclinical AD: in clinically normal older adults with abnormal β-amyloid (Aβ) deposition on positron emission tomography (PET) neuroimaging. METHOD Clinically normal older adults (mean Mini Mental State Exam (MMSE) score = 29) were classified as Aβ+ (n = 70) or Aβ- (n = 205) using Pittsburgh Compound B-(PET) imaging. Participants completed letter fluency (FAS; word generation to letters F-A-S) and category fluency (CAT; word generation to animals, vegetables, fruits) annually (mean follow-up = 2.42 years). The effect of Aβ status on fluency over time was examined using linear mixed models controlling for age, sex, and education. To dissociate effects related to semantic (CAT) versus retrieval processes (CAT and FAS), we repeated models predicting CAT over time, controlling for FAS and likewise for CAT controlling for FAS. RESULTS At baseline, the Aβ+ group performed better on FAS compared with the Aβ- group but comparably on CAT. Longitudinally, the Aβ+ group demonstrated greater decline on CAT compared with the Aβ- group (p = .0011). This finding remained significant even when covarying for FAS (p = .0107). Aβ+ participants similarly declined compared with Aβ- participants on FAS (p = .0112), but this effect became insignificant when covarying for CAT (p = .1607). CONCLUSION These findings provide biomarker validation for the greater specificity of declines in category versus letter fluency to underlying AD pathology. Our results also suggest that changes in semantic processing occur earlier in the AD trajectory than previously hypothesized. (PsycINFO Database Record

The Apathy Evaluation Scale: A Comparison of Subject, Informant, and Clinician Report in Cognitively Normal Elderly and Mild Cognitive Impairment

BACKGROUND Apathy is a common neuropsychiatric symptom in Alzheimers disease (AD) dementia and mild cognitive impairment (MCI). Detecting apathy accurately may facilitate earlier diagnosis of AD. The Apathy Evaluation Scale (AES) is a promising tool for measurement of apathy in prodromal and possibly preclinical AD. OBJECTIVE To compare the three AES sub-scales - subject-reported (AES-S), informant-reported (AES-I), and clinician-reported (AES-C) - over time in individuals at risk for AD due to MCI and advanced age (cognitively normal [CN] elderly). METHODS Mixed effects longitudinal models were used to assess predictors of score for each AES sub-scale. Cox proportional hazards models were used to assess which AES sub-scales predict progression from MCI to AD dementia. RESULTS Fifty-seven MCI and 18 CN subjects (ages 53-86) were followed for 1.4 ± 1.2 years and 0.7 ± 0.7 years, respectively. Across the three mixed effects longitudinal models, the common findings were associations between greater apathy and greater years in study, a baseline diagnosis of MCI (compared to CN), and male gender. CN elderly self-reported greater apathy compared to that reported by informants and clinicians, while individuals with MCI under-reported their apathy compared to informants and clinicians. Of the three sub-scales, the AES-C best predicted transition from MCI to AD dementia. CONCLUSION In a sample of CN elderly and elderly with MCI, apathy increased over time, particularly in men and those with MCI. AES-S scores may be more sensitive than AES-I and AES-C scores in CN elderly, but less reliable if subjects have MCI. Moreover, the AES-C sub-scale predicted progression from MCI to AD dementia.

Hippocampal hypometabolism in older adults with memory complaints and increased amyloid burden

Objective: To identify the functional and pathologic correlates underlying subjective memory complaints (SMCs) in cognitively normal older adults. Methods: Two hundred fifty-one older adults underwent resting-state fluorodeoxyglucose (FDG)-PET and Pittsburg compound B-PET β-amyloid (Aβ) imaging and filled out a questionnaire regarding SMCs. Participants were classified into 2 groups based on their Aβ burden. Age-adjusted voxel-wise correlations were used to examine SMCs, amyloid status (Aβ+ vs Aβ−), and the interaction between SMCs and Aβ status as predictors of metabolism. Region-of-interest (ROI) analyses were performed to confirm the whole-brain analyses and to test for additional covariates. Results: Greater SMCs correlated with decreased FDG metabolism in the bilateral precuneus, bilateral inferior parietal lobes, right inferior temporal lobe, right medial frontal gyrus, and right orbitofrontal gyrus. A significant interaction effect between SMCs and amyloid burden was found such that Aβ+ individuals with increased complaints had decreased FDG metabolism in the bilateral medial temporal lobes. ROI analyses confirmed the voxel-wise analyses result in that decreased precuneus metabolism was associated with greater SMCs regardless of Aβ status, age, or thickness, whereas the relationship between hippocampal metabolism and SMCs was a function of Aβ, even after adjustment for age, hippocampal volume, or depressive symptoms. Conclusions: These data show the relevant role of posterior and anterior midline regions in SMCs in older individuals. Decreased hippocampal metabolism may be a specific marker of subclinical changes in cognition due to amyloid pathology. However, longitudinal studies are needed to determine whether our findings foreshadow clinical decline.

Neuropsychiatric Symptoms and Functional Connectivity in Mild Cognitive Impairment

BACKGROUND Neuropsychiatric symptoms (NPS), such as apathy and depression, commonly accompany cognitive and functional decline in early Alzheimers disease (AD). Prior studies have shown associations between affective NPS and neurodegeneration of medial frontal and inferior temporal regions in mild cognitive impairment (MCI) and AD dementia. OBJECTIVE To investigate the association between functional connectivity in four brain networks and NPS in elderly with MCI. METHODS NPS were assessed using the Neuropsychiatric Inventory in 42 subjects with MCI. Resting-state functional connectivity in four networks (default mode network, fronto-parietal control network (FPCN), dorsal attention network, and ventral attention network) was assessed using seed-based magnetic resonance imaging. Factor analysis was used to identify two factors of NPS: Affective and Hyperactivity. Linear regression models were utilized with the neuropsychiatric factors as the dependent variable and the four networks as the predictors of interest. Covariates included age, gender, premorbid intelligence, processing speed, memory, head movement, and signal-to-noise ratio. These analyses were repeated with the individual items of the affective factor, using the same predictors. RESULTS There was a significant association between greater Affective factor symptoms and reduced FPCN connectivity (p = 0.03). There was no association between the Hyperactivity factor and any of the networks. Secondary analyses revealed an association between greater apathy and reduced FPCN connectivity (p = 0.005), but none in other networks. CONCLUSIONS Decreased connectivity in the FPCN may be associated with greater affective symptoms, particularly apathy, early in AD. These findings extend prior studies, using different functional imaging modalities in individuals with greater disease severity.

Anosognosia for memory deficits in mild cognitive impairment: Insight into the neural mechanism using functional and molecular imaging

Anosognosia, or loss of insight of memory deficits, is a common and striking symptom in Alzheimers disease (AD). Previous findings in AD dementia patients suggest that anosognosia is due to both functional metabolic changes within cortical midline structures involved in self-referential processes, as well as functional disconnection between these regions. The present study aims to extend these findings by investigating the neural correlates of anosognosia in the prodromal stage of AD. Here, we used regional brain metabolism (resting state 18-F fluorodeoxyglucose positron emission tomography (FDG-PET)) to unravel the metabolic correlates of anosognosia in subjects with amnestic mild cognitive impairment (aMCI) and subsequently resting state functional magnetic resonance imaging (rs-fMRI) to investigate the intrinsic connectivity disruption between brain regions. Thirty-one subjects (mean age: 74.1; Clinical Dementia Rating (CDR) global score: 0.5) with aMCI, and 251 cognitively normal (CN) older adults (mean age: 73.3; CDR: 0) were included as a reference group for behavioral and FDG data. An anosognosia index was obtained by calculating a discrepancy score between subjective and objective memory scores. All subjects underwent FDG-PET for glucose metabolism measurement, and aMCI subjects underwent additional rs-fMRI for intrinsic connectivity measurement. Voxel-wise correlations between anosognosia and neuroimaging data were conducted in the aMCI subjects. Subjects with aMCI had significantly decreased memory awareness as compared to the CN older adults. Greater anosognosia in aMCI subjects was associated with reduced glucose metabolism in the posterior cingulate (PCC) cortices and hippocampus. Intrinsic connectivity analyses revealed a significant association between anosognosia and attenuated functional connectivity between the PCC seed region and orbitofrontal cortex (OFC) as well as bilateral inferior parietal lobes (IPL). These findings provide further evidence that implicates cortical midline structures and hippocampus in the awareness of memory deficits. Investigating neuroimaging changes that co-vary with memory awareness may improve our ability to identify the cause of anosognosia and ultimately increase our chances for its treatment.

AB+ CLINICALLY NORMAL PARTICIPANTS WITH ELEVATED TAU SHOW GREATEST DECLINE IN THE PRECLINICAL ALZHEIMER’S DISEASE COGNITIVE COMPOSITE

nance imaging (MRI; 80.58 6 112.6 d AV-1451—PiB difference; 98.95 6 119.7 d AV-1451—MRI difference), with images transformed to a common space. We calculated each subject’s mean AV-1451 and PiB uptake values within 87 regions of interest (ROI), and a global cortical PiB value. We examined all pairwise ROI PiB—AV-1451 partial correlations for strength and significance to identify inter-tracer, interregional association patterns (covaried for age, sex, and global gray matter volume). Results: Pairwise ROI analysis demonstrated positive and negative PiB—AV-1451 associations (Figure 1). Importantly, strong (p < .01) positive partial correlations were identified between temporal AV-1451 and PIB in extensive temporal and extra-temporal cortical ROIs. We also found less frequent positive associations of regional PiB with frontoparietal AV-1451 (Figure 2). For AV-1451 ROIs where uptake was strongly predicted by PiB ROI (e.g., temporal, frontal AV-1451 uptake), these strong correlations were present regardless of PiB ROI location. Overall correlation strengths were visualized on a brain template (Figure 3). Conclusions:Ab and tau pathology, measured using PiB and AV-1451 PET, show significant associations among cognitively normal elderly. In particular, increased PiB uptake both within and outside temporal lobes correlates with increased temporal lobe AV-1451 uptake. In addition, the correlations between Ab and tau accumulation do not appear to be explained by the location of Ab accumulation. These results suggest a regional vulnerability of certain brain regions (e.g. temporal lobe) to tau accumulation regardless of where Ab accumulates.

THE IMPACT OF ANOSOGNOSIA AND ANOSODIAPHORIA ON THE PREDICTION OF PROGRESSION FROM MILD COGNITIVE IMPAIRMENT TO ALZHEIMER’S DISEASE

involved in self-referential processes as well as functional disconnection between these regions (Perrotin et al. 2015). The present study aims at extending these findings by better understanding the neural correlates of anosognosia in the prodromal stage of AD. Thus, here we used regional brain metabolism [FDG-PET] to unravel the metabolic correlates of anosognosia in patients with amnestic mild cognitive impairment (aMCI) and subsequently resting state fMRI [rs-fMRI] to investigate the intrinsic connectivity disruption between brain regions. Methods: Thirty-one subjects (mean age: 74.1; CDR: 0.5) with aMCI were included. All subjects underwent resting state 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) for glucose metabolism measurement and resting state fMRI for intrinsic connectivity measurement. An anosognosia index was obtained by calculating discrepancy scores between subjective and objective memory scores. Voxelwise correlations between anosognosia and neuroimaging data were conducted. All analyses were controlled for multiple comparison using pFDR 1⁄40.05. Results: Anosognosia in aMCI patients correlated with reduced glucose metabolism in posterior cingulate (PCC) cortices and hippocampus (Figure 1). Intrinsic connectivity analyses revealed a significant association between anosognosia and attenuated functional connectivity between the PCC seed region and orbitofrontal cortex (OFC) as well as bilateral inferior parietal lobes (IPL, Figure 2). Conclusions: These findings provide further evidence implicating cortical midline structures involved in awareness of memory deficits. MCI patients with anosognosia showed reduced metabolism as well as disconnection between OFC, PCC and hippocampus, brain regions vulnerable to changes in early Alzheimer’s disease, and therefore could be at increased risk of developing dementia. O4-06-05 MCI DIAGNOSIS: LESS IS MORE Liesbeth Aerts, John D. Crawford, Nicole A. Kochan, Megan Heffernan, Brian Draper, Julian N. Trollor, Perminder S. Sachdev, Henry Brodaty, Dementia Collaborative Research Centre, University of New SouthWales, Sydney, Australia; 2 Centre for Healthy Brain Ageing, UNSW, Sydney, Australia; 3 Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, Australia; Academic Department for Old Age Psychiatry, Prince of Wales Hospital, Randwick, Australia; 5 Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales, Sydney, Australia; Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia; 7 University of New South Wales, Sydney, Australia; 8 Centre for Healthy Brain Ageing UNSW Australia, Sydney, Australia; Dementia Collaborative Research Centre ABC, UNSWAustralia, Sydney, Australia. Contact e-mail: l.aerts@unsw.edu.au

NEUROIMAGING CORRELATES OF ANOSOGNOSIA IN MILD COGNITIVE IMPAIRMENT

averaged across voxels. Using voxel-based regression, we tested whether in MCI subjects higher education was associated with stronger FDG-PET hypometabolism, controlling for memory performance. In further regression analyses, we tested whether higher global LPFC connectivity was associated with higher education and reduced effects of FDG-PET hypometabolism onto episodic memory (interaction FDG-PET metabolism x global LPFC connectivity). Results: Higher education was associated with stronger precuneus FDG-PET hypometabolism in MCI-Ab+ but not MCIAbsubjects, when controlling for composite memory scores. This suggests that MCI-Ab+ with higher CR can better cope with FDG-PET hypometabolism. In the MCI-Ab+ subjects, higher education was associated with higher global LPFC connectivity. The interaction global LPFC connectivity x precuneus FDG-PET was significant in MCI-Ab+ subjects (p<0.05), such that at higher levels of LPFC global connectivity the association between precuneus FDG-PET hypometabolism and memory impairment was attenuated, suggesting compensatory effects of the LPFC (see Fig. 1). Conclusions: Higher global LPFC connectivity may contribute to higher CR and compensate FDG-PET hypometabolism in prodromal AD, thus allowing to maintain memory performance relatively well.

OPTIMAL MEMORY PERFORMANCE IN OLDER ADULTS IS ASSOCIATED WITH DIFFERENCES IN HIPPOCAMPAL VOLUME AND AMYLOID STATUS AT BASELINE AND OVER 3 YEARS

ADULTS IS ASSOCIATEDWITH DIFFERENCES IN HIPPOCAMPALVOLUME AND AMYLOID STATUS AT BASELINE AND OVER 3 YEARS Maria Dekhtyar, Kate V. Papp, Rebecca Amariglio, Yakeel T. Quiroz, Aaron P. Schultz, Catherine E. Munro, Emily P. Kilpatrick, Sarah L. Aghjayan, Sehily Y. Jaimes, Victoria H. Jonas, Molly R. LaPoint, Tamy-Fee Meneide, Kathryn P. Sparks, Keith Johnson, Reisa A. Sperling, DoreneM. Rentz, Massachusetts General Hospital, Boston,MA, USA; 2 Brigham and Women’s Hospital Center for Alzheimer Research and Treatment, Boston, MA, USA; 3 Harvard Medical School, Boston, MA, USA; Brigham and Women’s Hospital, Boston, MA, USA; Brigham and Women’s Hospital, Boston, MA, USA; Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital and the Athinoula A. Martinos Center for Biomedical Imaging, Boston, MA, USA; 9 Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; 11 Massachusetts General Hospital, Charlestown, MA, USA; 12 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 14 Department of Radiology, Division of Molecular Imaging and Nuclear Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging and the Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. Contact e-mail: mdekhtyar@ partners.org

Instrumental activities of daily living and functional connectivity in mild cognitive impairment

IC-P-071 INSTRUMENTAL ACTIVITIES OF DAILY LIVING AND FUNCTIONAL CONNECTIVITY IN MILD COGNITIVE IMPAIRMENT Gad A. Marshall, Catherine Munro, Sarah E. Wigman, Alex S. Dagley, Aaron P. Schultz, Rebecca Amariglio, Dorene M. Rentz, Keith A. Johnson, Reisa A. Sperling, Harvard Medical School, Boston, MA, USA; Brigham and Women’s Hospital, Boston, MA, USA; Massachusetts General Hospital, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital and the Athinoula A. Martinos Center for Biomedical Imaging, Boston, MA, USA. Contact e-mail: gamarshall@partners.org