Reisa A Sperling

Harvard Medical School, Boston, Massachusetts, United States

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Publications (309)3013.3 Total impact

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    ABSTRACT: The negative efficacy study examining the γ-secretase inhibitor semagacestat in mild to moderate Alzheimer's disease (AD) included a number of biomarkers of the disease as well as safety outcomes. We analyzed these data to explore relationships between drug exposure and pharmacodynamic effects and to examine the correlations among outcome measures. The study was a multicenter, randomized, placebo-controlled trial of two dose regimens of semagacestat and a placebo administered for 18 months to individuals with mild to moderate AD. Changes in measures of central and peripheral drug activity were compared between the three treatment groups using one-way analysis of variance. The relationship between changes in each of the outcome measures and measures of drug exposure and peripheral pharmacodynamic effect were assessed using Spearman's correlation coefficient. Assignment to the active treatment arms was associated with reduction in plasma amyloid-β (Aβ) peptides, increase in ventricular volume, decrease in cerebrospinal fluid phosphorylated tau (p-tau) and several other laboratory measures and adverse event categories. Within the active arms, exposure to drug, as indicated by area under the concentration curve (AUC) of blood concentration, was associated with reduction in plasma Aβ peptides and a subset of laboratory changes and adverse event rates. Ventricular volume increase, right hippocampal volume loss and gastrointestinal symptoms were related to change in plasma Aβ peptide but not AUC, supporting a link to inhibition of γ-secretase cleavage of the amyloid precursor protein. Cognitive decline correlated with ventricular expansion and reduction in p-tau. These findings may inform future studies of drugs targeting secretases involved in Aβ generation. ClinicalTrials.gov Identifier: NCT00594568. Registered 11 January 2008.
    Alzheimer's Research and Therapy 12/2015; 7(1). DOI:10.1186/s13195-015-0121-6 · 3.50 Impact Factor
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    ABSTRACT: Brain imaging and fluid biomarkers are characterized in children at risk for autosomal dominant Alzheimer disease (ADAD). To characterize and compare structural magnetic resonance imaging (MRI), resting-state and task-dependent functional MRI, and plasma amyloid-β (Aβ) measurements in presenilin 1 (PSEN1) E280A mutation-carrying and noncarrying children with ADAD. Cross-sectional measures of structural and functional MRI and plasma Aβ assays were assessed in 18 PSEN1 E280A carriers and 19 noncarriers aged 9 to 17 years from a Colombian kindred with ADAD. Recruitment and data collection for this study were conducted at the University of Antioquia and the Hospital Pablo Tobon Uribe in Medellín, Colombia, between August 2011 and June 2012. All participants had blood sampling, structural MRI, and functional MRI during associative memory encoding and resting-state and cognitive assessments. Outcome measures included plasma Aβ1-42 concentrations and Aβ1-42:Aβ1-40 ratios, memory encoding-dependent activation changes, resting-state connectivity, and regional gray matter volumes. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to AD. Similar to findings in adult mutation carriers, in the later preclinical and clinical stages of ADAD, mutation-carrying children were distinguished from control individuals by significantly higher plasma Aβ1-42 levels (mean [SD]: carriers, 18.8 [5.1] pg/mL and noncarriers, 13.1 [3.2] pg/mL; P < .001) and Aβ1-42:Aβ1-40 ratios (mean [SD]: carriers, 0.32 [0.06] and noncarriers, 0.21 [0.03]; P < .001), as well as less memory encoding task-related deactivation in parietal regions (eg, mean [SD] parameter estimates for the right precuneus were -0.590 [0.50] for noncarriers and -0.087 [0.38] for carriers; P < .005 uncorrected). Unlike carriers in the later stages, mutation-carrying children demonstrated increased functional connectivity of the posterior cingulate cortex with medial temporal lobe regions (mean [SD] parameter estimates were 0.038 [0.070] for noncarriers and 0.190 [0.057] for carriers), as well as greater gray matter volumes in temporal regions (eg, left parahippocampus; P < . 049, corrected for multiple comparisons). Children at genetic risk for ADAD have functional and structural brain changes and abnormal levels of plasma Aβ1-42. The extent to which the underlying brain changes are either neurodegenerative or developmental remains to be determined. This study provides additional information about the earliest known biomarker changes associated with ADAD.
    06/2015; DOI:10.1001/jamaneurol.2015.1099
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    ABSTRACT: We aimed to determine whether there was a relationship between lifestyle factors and Alzheimer disease biomarkers. In a cross-sectional study, we evaluated self-reported histories of recent and past cognitive activity, self-reported history of recent physical activity, and objective recent walking activity in 186 clinically normal individuals with mean age of 74 ± 6 years. Using backward elimination general linear models, we tested the hypotheses that greater cognitive or physical activity would be associated with lower Pittsburgh compound B-PET retention, greater (18)F-fluorodeoxyglucose-PET metabolism, and larger hippocampal volume, as well as better cognitive performance on neuropsychological testing. Linear regression demonstrated that history of greater cognitive activity was correlated with greater estimated IQ and education, as well as better neuropsychological testing performance. Self-reported recent physical activity was related to objective exercise monitoring. However, contrary to hypotheses, we did not find evidence of an association of Pittsburgh compound B retention, (18)F-fluorodeoxyglucose uptake, or hippocampal volume with past or current levels of cognitive activity, or with current physical activity. We conclude that a history of lifelong cognitive activity may support better cognitive performance by a mechanism that is independent of brain β-amyloid burden, brain glucose metabolism, or hippocampal volume. © 2015 American Academy of Neurology.
    Neurology 06/2015; DOI:10.1212/WNL.0000000000001704 · 8.30 Impact Factor
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    ABSTRACT: To determine whether neuroimaging biomarkers of amyloid-β (Aβ) and neurodegeneration (ND) are associated with greater self-reported subjective cognitive concerns (SCC) in clinically normal older individuals. A total of 257 participants underwent Pittsburgh compound B PET, PET with fluorodeoxyglucose (18)F, and structural MRI, as well as a battery of neuropsychological measures including several questionnaires regarding SCC. Individuals were classified into 4 biomarker groups: biomarker negative (Aβ-/ND-), amyloidosis alone (Aβ+/ND-), amyloidosis plus ND (Aβ+/ND+), and ND alone (Aβ-/ND+). Both Aβ and ND were independently associated with greater SCC controlling for objective memory performance. By contrast, neither Aβ nor ND was associated with objective memory performance controlling for SCC. Further examination revealed greater SCC in individuals with Aβ or ND positivity compared to biomarker-negative individuals. In addition, greater SCC predicted Aβ positivity when controlling for ND status. When individuals were grouped by biomarker status, those who were positive on Aβ or ND had the highest report of SCC compared to biomarker-negative individuals. Findings were consistent when SCC was used to predict Aβ positivity. Taken together, results suggest that both Aβ and ND are associated with SCC, independent of objective memory performance. Enrichment of individuals with SCC may increase likelihood of Aβ and ND markers in potential participants for secondary prevention trials. © 2015 American Academy of Neurology.
    Neurology 06/2015; DOI:10.1212/WNL.0000000000001712 · 8.30 Impact Factor
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    ABSTRACT: Furthering our understanding of the relationship between amyloidosis (Aβ), neurodegeneration (ND), and cognition is imperative for early identification and early intervention of Alzheimer's disease (AD). However, the subtle cognitive decline differentially associated with each biomarker-defined stage of preclinical AD has yet to be fully characterized. Recent work indicates that different components of memory performance (free and cued recall) may be differentially specific to memory decline in prodromal AD. We sought to examine the relationship between free and cued recall paradigms, in addition to global composites of memory, executive functioning, and processing speed in relation to stages of preclinical AD.
    Neuropsychologia 05/2015; 73. DOI:10.1016/j.neuropsychologia.2015.04.034 · 3.45 Impact Factor
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    ABSTRACT: Our objective was to investigate cross-sectional associations between odor identification ability and imaging biomarkers of neurodegeneration and amyloid deposition in clinically normal (CN) elderly individuals, specifically testing the hypothesis that there may be an interaction between amyloid deposition and neurodegeneration in predicting odor identification dysfunction. Data were collected on 215 CN participants from the Harvard Aging Brain Study. Measurements included the 40-item University of Pennsylvania Smell Identification Test and neuropsychological testing, hippocampal volume (HV) and entorhinal cortex (EC) thickness from MRI, and amyloid burden using Pittsburgh compound B (PiB) PET. A linear regression model with backward elimination (p < 0.05 retention) evaluated the cross-sectional association between the University of Pennsylvania Smell Identification Test and amyloid burden, HV, and EC thickness, assessing for effect modification by PiB status. Covariates included age, sex, premorbid intelligence, APOE ε4 carrier status, and Boston Naming Test. In unadjusted univariate analyses, worse olfaction was associated with decreased HV (p < 0.001), thinner EC (p = 0.003), worse episodic memory (p = 0.03), and marginally associated with greater amyloid burden (binary PiB status, p = 0.06). In the multivariate model, thinner EC in PiB-positive individuals (interaction term) was associated with worse olfaction (p = 0.02). In CN elderly, worse odor identification was associated with markers of neurodegeneration. Furthermore, individuals with elevated cortical amyloid and thinner EC exhibited worse odor identification, elucidating the potential contribution of olfactory testing to detect preclinical AD in CN individuals. © 2015 American Academy of Neurology.
    Neurology 05/2015; 84(21). DOI:10.1212/WNL.0000000000001614 · 8.30 Impact Factor
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    ABSTRACT: Neuropsychiatric symptoms (NPS), such as apathy and depression, commonly accompany cognitive and functional decline in early Alzheimer's 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. To investigate the association between functional connectivity in four brain networks and NPS in elderly with MCI. 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. 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. 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.
    Journal of Alzheimer's disease: JAD 04/2015; DOI:10.3233/JAD-150017 · 3.61 Impact Factor
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    ABSTRACT: The Harvard Aging Brain Study is sharing its data with the global research community. The longitudinal dataset consists of a 284-subject cohort with the following modalities acquired: demographics, clinical assessment, comprehensive neuropsychological testing, clinical biomarkers, and neuroimaging. To promote more extensive analyses, imaging data was designed to be compatible with other publicly available datasets. A cloud-based system enables access to interested researchers with blinded data available contingent upon completion of a data usage agreement and administrative approval. Data collection is ongoing and currently in its fifth year. Copyright © 2015. Published by Elsevier Inc.
    NeuroImage 04/2015; DOI:10.1016/j.neuroimage.2015.03.069 · 6.13 Impact Factor
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    ABSTRACT: Intrinsic functional connectivity MRI has become a widely-used tool for measuring integrity in large-scale cortical networks. This study examined multiple cortical networks using Template-Based Rotation (TBR), a method that applies a priori network and nuisance component templates defined from an independent dataset to test datasets of interest. A priori templates were applied to a test dataset of 276 older adults (ages 65-90) from the Harvard Aging Brain Study to examine the relationship between multiple large-scale cortical networks and cognition. Factor scores derived from neuropsychological tests represented processing speed, executive function, and episodic memory. Resting-state BOLD data were acquired in two six-minute acquisitions on a 3-Telsa scanner and processed with TBR to extract individual-level metrics of network connectivity in multiple cortical networks. All results controlled for data quality metrics including motion. Connectivity in multiple large-scale cortical networks was positively related to all cognitive domains, with a composite measure of general connectivity positively associated with general cognitive performance. Controlling for the correlations between networks, the fronto-parietal control network and executive function demonstrated the only significant association, suggesting specificity in this relationship. Further analyses found that the fronto-parietal control network mediated the relationships of the other networks with cognition, suggesting that this network may play a central role in understanding individual variation in cognition during aging.
    04/2015; DOI:10.1089/brain.2014.0327
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    ABSTRACT: Objective Aging is associated with reduced neural integrity, yet there are remarkable individual differences in brain health among older adults (OA). One factor that may attenuate age-related neural decline is cardiorespiratory fitness (CRF). The primary aim of this study was to link CRF to neural white matter microstructure using diffusion tensor imaging in OA.Methods Young adults (YA; n = 32) and OA (n = 27) completed a graded maximal exercise test to evaluate CRF and diffusion tensor magnetic resonance imaging to examine neural white matter integrity.ResultsAs expected, pervasive age-related declines in white matter integrity were observed when OA were compared to YA. Further, peak VO2 was positively associated with fractional anisotropy (FA), an indicator of white matter integrity, in multiple brain regions in OA, but not YA. In multiple posterior regions such as the splenium, sagittal stratum, posterior corona radiata, and superior parietal white matter, FA values were similar in YA and OA classified as higher fit, with both groups having greater FA than lower fit OA. However, age-related differences in FA values remained in other regions, including the body and genu of the corpus callosum, precuneus, and superior frontal gyrus.InterpretationCRF is positively associated with neural white matter microstructure in aging. The relationship between peak VO2 and FA appears to be tract-specific, as equivalent FA values were observed in higher fit OA and YA in some white matter tracts, but not others. Further, the association between peak VO2 and FA appears to be age-dependent.
    04/2015; 2(6). DOI:10.1002/acn3.204
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    ABSTRACT: Alzheimer disease has a long preclinical stage characterized by β-amyloid (Aβ) accumulation without symptoms. Several trials focus on this stage and use biomarkers to include Aβ-positive participants, but an even earlier prevention of Aβ accumulation may be an effective treatment strategy. To determine whether people who appear to be Aβ negative but are at high risk for Aβ positivity within the near future can be identified. Longitudinal biomarker cohort study involving 35 cognitively healthy individuals who underwent cerebrospinal fluid (CSF) sampling for up to 3 years during the study (October 24, 2005, to September 1, 2014). All participants had normal CSF Aβ42 levels at baseline. Predictors of future Aβ positivity (levels of CSF Aβ42 declining below a previously validated cutoff level of 192 ng/L) tested by random forest models. Tested predictors included levels of protein in the CSF, hippocampal volume, genetics, demographics, and cognitive scores. The CSF Aβ42 levels declined in 11 participants, and the CSF became Aβ positive. The baseline CSF Aβ42 level was a strong predictor of future positivity (accuracy, 79% [95% CI, 70%-87%]). Ten of 11 decliners had baseline CSF Aβ42 levels in the lower tertile of the reference range (<225 ng/L), and 22 of 24 nondecliners had baseline CSF Aβ42 levels in the upper 2 tertiles (≥225 ng/L). A high CSF P-tau level was associated with decline (accuracy, 68%; 95% CI, 55%-81%). Baseline CSF Aβ42 levels in the lower part of the reference range are strongly associated with future Aβ positivity. This finding can be used in trials on very early prevention of Alzheimer disease to identify people at high risk for Aβ accumulation as defined by low CSF Aβ42 levels.
    JAMA Neurology 03/2015; 72(5). DOI:10.1001/jamaneurol.2014.4530 · 7.01 Impact Factor
  • American Journal of Geriatric Psychiatry 03/2015; 23(3):S96-S97. DOI:10.1016/j.jagp.2014.12.098 · 3.52 Impact Factor
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    ABSTRACT: Combination therapy has proven to be an effective strategy for treating many of the world's most intractable diseases. A growing number of investigators in academia, industry, regulatory agencies, foundations and advocacy organizations are interested in pursuing a combination approach to treating Alzheimer's disease. A meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer's Disease Coalition, the Critical Path Institute and the Alzheimer's Association addressed challenges in designing clinical trials to test multiple treatments in combination and outlined a roadmap for making such trials a reality.
    Expert Review of Neurotherapeutics 03/2015; 15(3):327-33. DOI:10.1586/14737175.2015.996551 · 2.83 Impact Factor
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    ABSTRACT: Several large-scale Alzheimer disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures that are sensitive to early clinical progression in individuals who are initially asymptomatic. To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline. Longitudinal study from February 2002 through February 2007 at participating Alzheimer's Disease Cooperative Study sites. Individuals were followed up annually for 48 months after the baseline visit. The study included 468 healthy older individuals (Clinical Dementia Rating scale [CDR] global scores of 0, above cutoff on the modified Mini-Mental State Examination and Free and Cued Selective Reminding Test) (mean [SD] age, 79.4 [3.6] years; age range, 75.0-93.8 years). All study participants and their study partners completed the self and partner CFIs annually. Individuals also underwent concurrent annual neuropsychological assessment and APOE genotyping. The CFI scores between clinical progressors (CDR score, ≥0.5) and nonprogressors (CDR score, 0) and between APOE ε4 carriers and noncarriers were compared. Correlations of change between the CFI scores and neuropsychological performance were assessed longitudinally. At 48 months, group differences between clinical progressors and non-progressors were significant for self (2.13, SE=0.45, P < .001), partner (5.08, SE=0.59, P < .001), and self plus partner (7.04, SE=0.83, P < .001) CFI total scores. At month 48, APOE ε4 carriers had greater progression than noncarriers on the partner (1.10, SE=0.44, P < .012) and self plus partner (1.56, SE=0.63, P < .014) CFI scores. Both self and partner CFI change were associated with longitudinal cognitive decline (self, ρ=0.32, 95% CI, 0.13 to 0.46; partner, ρ=0.56, 95% CI, 0.42 to 0.68), although findings suggest self-report may be more accurate early in the process, whereas accuracy of partner report improves when there is progression to cognitive impairment. Demonstrating long-term clinical benefit will be critical for the success of recently launched secondary prevention trials. The CFI appears to be a brief, but informative potential outcome measure that provides insight into functional abilities at the earliest stages of disease.
    JAMA Neurology 02/2015; 72(4). DOI:10.1001/jamaneurol.2014.3375 · 7.01 Impact Factor
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    ABSTRACT: Even low levels of depressive symptoms are associated with an increased risk of cognitive decline in older adults without overt cognitive impairment (CN). Our objective was to examine whether very low, "subthreshold symptoms of depression" are associated with Alzheimer's disease (AD) biomarkers of neurodegeneration in CN adults and whether these associations are specific to particular depressive symptoms. We analyzed data from 248 community-dwelling CN older adults, including measurements of cortical amyloid burden, neurodegeneration markers of hippocampal volume (HV) and cerebral 18F-fluorodeoxyglucose (FDG) metabolism in a composite of AD-related regions and the 30-item Geriatric Depression Scale (GDS). Participants with GDS >10 were excluded. General linear regression models evaluated the cross-sectional relations of GDS to HV or FDG in separate backward elimination models. Predictors included GDS total score, age, gender, premorbid intelligence, a binary amyloid variable and its interaction with GDS. Principal component analyses of GDS item scores revealed three factors (the Dysphoria, Apathy-Anhedonia, and Anxiety-Concentration Factors). In secondary analyses, GDS total score was replaced with the three factor scores in repeated models. Higher GDS score (p = 0.03) was significantly associated with lower HV and was marginally related (p = 0.06) to FDG hypometabolism. In secondary models, higher Dysphoria (p = 0.02) and Apathy-Anhedonia (p = 0.05) were related to lower HV while higher Apathy-Anhedonia (p = 0.003) was the sole factor related to FDG hypometabolism. Amyloid was not a significant predictor in any model. In conclusion, very low-level dysphoria, apathy and anhedonia may point to neurodegeneration in AD-related regions but this association appears to be independent of amyloid burden.
    Journal of Alzheimer's disease: JAD 02/2015; 46(1). DOI:10.3233/JAD-142940 · 3.61 Impact Factor
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    ABSTRACT: Willem Huijbers1,2, Elizabeth C. Mormino1,3, Aaron P. Schultz3, Sarah Wigman1,2, Andrew M. Ward1,2,4, Mykol Larvie2,3, Rebecca E. Amariglio1,2, Gad A. Marshall1,2, Dorene M. Rentz1,2, Keith A. Johnson2,3 and Reisa A. Sperling1,2,31 Centre for Alzheimer Research and Treatment, Department of Neurology, Brigham and Womentextquoterights Hospital, Harvard Medical School, Boston, MA, USA2 Athinoula A. Martinos Centre for Biomedical Imaging, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA3 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA4 Helen Willis Neuroscience Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USACorrespondence to: Willem Huijbers, Martinos Centre for Biomedical Imaging, 149 13th Street, Charlestown MA 02129 E-mail: w.huijbersatgmail.comReceived August 5, 2014.Revision received November 2, 2014.Accepted November 22, 2014.Summary Cross-sectional functional magnetic resonance imaging studies using a memory task in patients with mild cognitive impairment have produced discordant results, with some studies reporting increased hippocampal activitytextemdashconsistent with findings in genetic at-risk populationstextemdashand other studies reporting decreased hippocampal activity, relative to normal controls. However, previous studies in mild cognitive impairment have not included markers of amyloid-β, which may be particularly important in prediction of progression along the Alzheimertextquoterights disease continuum. Here, we examine the contribution of amyloid-β deposition to cross-sectional and longitudinal measures of hippocampal functional magnetic resonance imaging activity, hippocampal volume, global cognition and clinical progression over 36 months in 33 patients with mild cognitive impairment. Amyloid-β status was examined with positron emission tomography imaging using Pittsburg compound-B, hippocampal functional magnetic resonance imaging activity was assessed using an associative face-name memory encoding task, and hippocampal volume was quantified with structural magnetic resonance imaging. Finally global cognition was assessed using the Mini-Mental State Examination and clinical progression was assessed using the Clinical Dementia Rating (Sum of Boxes). At baseline, amyloid-β positive patients with mild cognitive impairment showed increased hippocampal activation, smaller hippocampal volumes, and a trend towards lower Mini-Mental State Examination scores and higher Clinical Dementia Ratings compared to amyloid-β negative patients with mild cognitive impairment. Longitudinally, amyloid-β positive patients with mild cognitive impairment continued to show high levels of hippocampal activity, despite increasing rates of hippocampal atrophy, decline on the Mini-Mental State Examination and faster progression on the Clinical Dementia Ratings. When entered simultaneously into the same linear mixed model, amyloid-β status, hippocampal activation, and hippocampal volume independently predicted clinical progression. These results indicate that amyloid-β positive patients with mild cognitive impairment are more likely on a path towards Alzheimertextquoterights disease dementia than amyloid-β negative patients. Increased hippocampal activity is discussed in relation to neuronal compensation and/or amyloid-β induced excitoxicity. amyloid depositionMCIhippocampal activationfunctional MRIclinical progressionAbbreviationsDVRdistribution volume ratioMCImild cognitive impairmentPiBPittsburg compound-Btextcopyright The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com
    Brain 02/2015; 10(4). DOI:10.1093/brain/awv007 · 10.23 Impact Factor
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    ABSTRACT: Apathy is a common neuropsychiatric symptom in Alzheimer's disease dementia and amnestic mild cognitive impairment and is associated with cortical atrophy in Alzheimer's disease dementia. This study investigated possible correlations between apathy and cortical atrophy in 47 individuals with mild cognitive impairment and 19 clinically normal elderly. Backward elimination multivariate linear regression was used to evaluate the cross-sectional relationship between scores on the Apathy Evaluation Scale and thickness of several cortical regions and covariates. Lower inferior temporal cortical thickness was predictive of greater apathy. Greater anterior cingulate cortical thickness was also predictive of greater apathy, suggesting an underlying reactive process.
    The Journal of neuropsychiatry and clinical neurosciences 01/2015; 27(1):e22-7. DOI:10.1176/appi.neuropsych.13060141 · 2.77 Impact Factor
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    ABSTRACT: It is acknowledged that progress in combined therapeutic approaches for Alzheimer's disease (AD) will require an unprecedented level of collaboration. At a meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer's Disease Coalition and the Critical Path Institute, investigators from industry, academia and regulatory agencies agreed on the need for combinatorial approaches to treating AD. The need for advancing multiple targets includes recognition for novel adaptive trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination. A combination trial now being planned may test drugs targeting different pathogenic pathways or multiple targets along a common pathway. Collaborations and consortia-based strategies are pivotal for success and a regulatory framework is recommended for success.
    Expert Review of Neurotherapeutics 12/2014; 15(1):1-7. DOI:10.1586/14737175.2015.995168 · 2.83 Impact Factor
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    ABSTRACT: Amyloid imaging is a valuable tool for research and diagnosis in dementing disorders. As positron emission tomography (PET) scanners have limited spatial resolution, measured signals are distorted by partial volume effects. Various techniques have been proposed for correcting partial volume effects, but there is no consensus as to whether these techniques are necessary in amyloid imaging, and, if so, how they should be implemented. We evaluated a two-component partial volume correction technique and a regional spread function technique using both simulated and human Pittsburgh compound B (PiB) PET imaging data. Both correction techniques compensated for partial volume effects and yielded improved detection of subtle changes in PiB retention. However, the regional spread function technique was more accurate in application to simulated data. Because PiB retention estimates depend on the correction technique, standardization is necessary to compare results across groups. Partial volume correction has sometimes been avoided because it increases the sensitivity to inaccuracy in image registration and segmentation. However, our results indicate that appropriate PVC may enhance our ability to detect changes in amyloid deposition. Copyright © 2014. Published by Elsevier Inc.
    NeuroImage 12/2014; 107. DOI:10.1016/j.neuroimage.2014.11.058 · 6.13 Impact Factor
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    ABSTRACT: Objective Genome-wide association studies have linked variants in TREM2 (triggering receptor expressed on myeloid cells 2) and TREML2 with Alzheimer disease (AD) and AD endophenotypes. Here, we pursue a targeted analysis of the TREM locus in relation to cognitive decline and pathological features of AD.Methods Clinical, cognitive, and neuropathological phenotypes were collected in 3 prospective cohorts on aging (n = 3,421 subjects). Our primary analysis was an association with neuritic plaque pathology. To functionally characterize the associated variants, we used flow cytometry to measure TREM1 expression on monocytes.ResultsWe provide evidence that an intronic variant, rs6910730G, in TREM1, is associated with an increased burden of neuritic plaques (p = 3.7 × 10−4), diffuse plaques (p = 4.1 × 10−3), and Aβ density (p = 2.6 × 10−3) as well as an increased rate of cognitive decline (p = 5.3 × 10−3). A variant upstream of TREM2, rs7759295C, is independently associated with an increased tau tangle density (p = 4.9 × 10−4), an increased burden of neurofibrillary tangles (p = 9.1 × 10−3), and an increased rate of cognitive decline (p = 2.3 × 10−3). Finally, a cytometric analysis shows that the TREM1 rs6910730G allele is associated with decreased TREM1 expression on the surface of myeloid cells (p = 1.7 × 10−3).InterpretationWe provide evidence that 2 common variants within the TREM locus are associated with pathological features of AD and aging-related cognitive decline. Our evidence suggests that these variants are likely to be independent of known AD variants and that they may work through an alteration of myeloid cell function. Ann Neurol 2015;77:469-477
    Annals of Neurology 12/2014; 77(3). DOI:10.1002/ana.24337 · 11.91 Impact Factor

Publication Stats

11k Citations
3,013.30 Total Impact Points

Institutions

  • 2007–2015
    • Harvard Medical School
      • • Department of Neurology
      • • Athinoula A. Martinos Center for Biomedical Imaging
      Boston, Massachusetts, United States
    • University of Kuopio
      Kuopio, Northern Savo, Finland
  • 2002–2015
    • Massachusetts General Hospital
      • • Department of Neurology
      • • Division of Nuclear Medicine and Molecular Imaging
      • • Department of Radiology
      • • Athinoula A. Martinos Center for Biomedical Imaging
      Boston, Massachusetts, United States
  • 2001–2015
    • Brigham and Women's Hospital
      • • Department of Neurology
      • • Division of Cognitive and Behavioral Neurology
      Boston, Massachusetts, United States
  • 2001–2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2013
    • University of Pennsylvania
      Filadelfia, Pennsylvania, United States
    • Alzheimer's Association
      Chicago, Illinois, United States
    • University of Melbourne
      Melbourne, Victoria, Australia
  • 2011–2013
    • Washington University in St. Louis
      • Department of Neurology
      San Luis, Missouri, United States
    • Banner Alzheimer's Institute
      Phoenix, Arizona, United States